S-enantiomerically enriched compositions of beta blockers for treating amyotrophic lateral sclerosis

ABSTRACT

The present invention relates to S-enantiomerically enriched compositions of beta blockers and uses thereof, including uses of the beta blocker compositions for treating amyotrophic lateral sclerosis. The beta blocker compositions can also be used for preventing loss of lean mass, preventing body weight loss in subjects, improving quality of life in subjects, and prolonging survival in amyotrophic lateral sclerosis patients. The beta blocker can be oxprenolol or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. Provisional PatentApplication Ser. No. 61/786,235, filed Mar. 14, 2013, which isincorporated herein by reference in its entirety.

TECHNICAL FIELD

The present invention relates to S-enantiomerically enrichedcompositions of beta blockers or pharmaceutically acceptable saltsthereof and uses thereof, including uses of the beta blockercompositions for treating amyotrophic lateral sclerosis. The betablocker can be oxprenolol or a pharmaceutically acceptable salt thereof.

BACKGROUND

Amyotrophic lateral sclerosis (ALS) covers a spectrum ofneurodegenerative syndromes characterized by progressive muscularparalysis reflecting degeneration of motor neurons in the brain andspinal cord. ALS is one of the most common neurodegenerative disorders,with an incidence of 1 to 2 per 100,000 and a prevalence of 4 to 6 per100,000; as many as 30,000 Americans have the disease at any given time(Worms P M. The epidemiology of motor neuron disease: a review of recentstudies. J Neurol Sci 2001, 191:3-9). The incidence in males is higherthan in females (1.6:1). 5-10% of patients have a positive familyhistory of ALS, most commonly with an autosomal dominant inheritancepattern. ALS is a disease of mature adults, with a median age of onsetof 55 years and its frequency increases with age until age 75. Overall50% of patients die within the first three years since the firstclinical manifestations. Apart from age or a positive family history, anumber of factors and environmental toxins have been further studied asrisk factors. A high relative risk was described in smokers, soccerplayers, especially Italians and veterans of the Gulf War.

Oxprenolol is a non-selective beta blocker which possesses someintrinsic sympathomimetic activity. Because of its beta blockerfunction, oxprenolol has been used for the treatment of various diseasessuch as angina pectoris, abnormal heart rhythms, and high bloodpressure. Oxprenolol is lipophilic and crosses the blood-brain barriermore easily than other more water soluble beta blockers. As a result,oxprenolol is associated with a higher incidence of CNS-related sideeffects than other beta blockers, but also has more central CNS modes ofaction.

The disclosure of all publications, patents, patent applications, andpublished patent applications referred to herein are hereby incorporatedherein by reference in their entirety.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to S-enantiomerically enrichedcompositions of beta blockers or pharmaceutically acceptable saltsthereof and uses thereof, including uses of the beta blockercompositions for treating amyotrophic lateral sclerosis. The betablocker can be oxprenolol or a pharmaceutically acceptable salt thereof.

The present disclosure provides, in some embodiments, a method oftreating amyotrophic lateral sclerosis in an individual havingamyotrophic lateral sclerosis, comprising administering to theindividual an effective amount of a composition comprising a betablocker or a pharmaceutically acceptable salt thereof, wherein betablocker has one chiral center and the composition is enantiomericallyenriched for the S-enantiomer.

The present disclosure provides, in some embodiments, a method ofprolonging survival of an individual having amyotrophic lateralsclerosis, comprising administering to the individual an effectiveamount of a composition comprising a beta blocker or a pharmaceuticallyacceptable salt thereof, wherein beta blocker has one chiral center andthe composition is enantiomerically enriched for the S-enantiomer.

The present disclosure provides, in some embodiments, a method ofdelaying the development of amyotrophic lateral sclerosis in anindividual having amyotrophic lateral sclerosis, comprisingadministering to the individual an effective amount of a compositioncomprising a beta blocker or a pharmaceutically acceptable salt thereof,wherein beta blocker has one chiral center and the composition isenantiomerically enriched for the S-enantiomer.

The present disclosure provides, in some embodiments, a method ofpreventing loss of lean mass of an individual having amyotrophic lateralsclerosis, comprising administering to the individual an effectiveamount of a composition comprising a beta blocker or a pharmaceuticallyacceptable salt thereof, wherein beta blocker has one chiral center andthe composition is enantiomerically enriched for the S-enantiomer.

The present disclosure provides, in some embodiments, a method ofpreventing muscle wasting of an individual having amyotrophic lateralsclerosis, comprising administering to the individual an effectiveamount of a composition comprising a beta blocker or a pharmaceuticallyacceptable salt thereof, wherein beta blocker has one chiral center andthe composition is enantiomerically enriched for the S-enantiomer.

The present disclosure provides, in some embodiments, a method ofimproving quality of life in an individual having amyotrophic lateralsclerosis, comprising administering to the individual an effectiveamount of a composition comprising a beta blocker or a pharmaceuticallyacceptable salt thereof, wherein beta blocker has one chiral center andthe composition is enantiomerically enriched for the S-enantiomer.

In some embodiments, the beta blocker is oxprenolol or apharmaceutically acceptable salt thereof. In some embodiments, the betablocker is oxprenolol or a pharmaceutically acceptable salt thereof,wherein the composition is enantiomerically enriched for S-oxprenolol.In some embodiments, the composition comprises an enantiomeric excess ofat least about 50% of S-oxprenolol. In some embodiments, the compositioncomprises an enantiomeric excess of at least about 80% of S-oxprenolol.In some embodiments, the composition comprises an enantiomeric excess ofat least about 99% of S-oxprenolol. In some embodiments, the compositioncomprises an enantiomeric excess of at least 99.9% of S-oxprenolol. Insome embodiments, the amyotrophic lateral sclerosis is sporadicamyotrophic lateral sclerosis. In some embodiments, the amyotrophiclateral sclerosis is familial amyotrophic lateral sclerosis. In someembodiments, the amyotrophic lateral sclerosis is Western Pacificamyotrophic lateral sclerosis. In some embodiments, the amyotrophiclateral sclerosis is juvenile amyotrophic lateral sclerosis. In someembodiments, the amyotrophic lateral sclerosis is Hiramaya Disease. Insome embodiments, the amyotrophic lateral sclerosis is progressivebulbhar palsy (PBP), progressive muscular atrophy (PMA), primary lateralsclerosis (PLS), or ALS with multi-system involvement. In someembodiments, the composition is administered orally. In someembodiments, the amount of S-oxprenolol in the composition is about 80to about 160 mg daily. In some embodiments, the composition isadministered daily or twice daily.

The present disclosure provides, in some embodiments, a kit comprising apharmaceutical composition comprising a composition comprising a betablocker or a pharmaceutically acceptable salt thereof, wherein betablocker has one chiral center and the composition is enantiomericallyenriched for the S-enantiomer; and a pharmaceutically acceptable carrierfor treating amyotrophic lateral sclerosis. In some embodiments, thebeta blocker is oxprenolol.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram showing a clinical symptomatological evaluation ofthe B6SJL-Tg(SOD1*G93A)1Gur/J ALS transgenic mouse.

FIG. 2 is a graph showing the percent survival of mice populations thatwere administered with S-oxprenolol or a placebo (plac). The sample sizein the population is indicated by “n.”

FIG. 3 is a graph showing the percent survival of mice populations thatwere administered S-oxprenolol. S-pindolol, or a placebo. The samplesize in the population is indicated by “n.” “HR” refers to hazard ratio.“CI” refers to confidence interval. “95% CI” is 95% confidence interval.“p” refers to p-value.

FIG. 4 is a graph showing the percent survival of mice populations thatwere administered S-oxprenolol (sox10), R-oxprenolol (rox10), oxprenolol(ox20), riluzole (riluzole), propanolol (prop), or a placebo (plac). Thesample size in the population is indicated by “n.” “HR” refers to hazardratio. “CI” refers to confidence interval. “95% CI” is 95% confidenceinterval. “p” refers to p-value.

FIG. 5 is a graph showing the change in body weight per survival dayafter ALS onset of mice populations that were administered with variousdosages of the S-oxprenolol, S-pindolol, or a placebo. The sample sizein the population is indicated by “n.”

FIG. 6 is a graph showing the change in lean body mass (in grams (“g”))of mice populations that were administered with S-oxprenolol or aplacebo.

FIG. 7 is a graph showing the change in lean body mass per survival dayafter ALS onset of mice populations that were administered withS-oxprenolol, S-pindolol, or a placebo. The asterisk (*) indicates thatthe p value is less than 0.05 versus placebo.

FIG. 8 is a graph showing the mass of gastrocnemius muscle (in grams(“g”)) in mice populations that were administered a placebo.

FIG. 9 is a graph showing the mass of gastrocnemius muscle (in grams(“g”)) in mice populations that were administered S-oxprenolol.

FIG. 10 is a graph showing the mass of tibialis anterior muscle (ingrams (“g”)) in mice populations that were administered a placebo.

FIG. 11 is a graph showing the mass of tibialis anterior muscle (ingrams (“g”)) in mice populations that were administered S-oxprenolol.

FIG. 12 is a graph showing the change in fat mass (in grams (“g”)) ofmice populations that were administered S-oxprenolol or a placebo.

FIG. 13 is a graph showing the change in fat mass per survival day afterALS onset of mice populations that were administered with S-oxprenolol,S-pindolol, or a placebo. The asterisk (*) indicates that the p value isless than 0.05 versus placebo.

FIG. 14 is a graph showing the percent survival of mice populations thatwere administered with S-oxprenolol, rilutek, propanolol, oxprenolol(racemic), or R-oxprenolol. The sample size in the population isindicated by “n.”

FIG. 15 is a graph showing the percent survival of male mice populationsthat were administered with S-oxprenolol, rilutek, propanolol,oxprenolol (racemic), or R-oxprenolol. The sample size in the populationis indicated by “n.”

FIG. 16 is a graph showing the percent survival of female micepopulations that were administered with S-oxprenolol, rilutek,propanolol, oxprenolol (racemic), or R-oxprenolol. The sample size inthe population is indicated by “n.”

FIG. 17 is a graph showing the change in disease progression scored fromscore 1 to score 2 of mice populations that were administered withS-oxprenolol, rilutek, propanolol, oxprenolol (racemic), orR-oxprenolol.

FIG. 18 is a graph showing the change in disease progression scored fromscore 2 to score 3 of mice populations that were administered withS-oxprenolol, rilutek, propanolol, oxprenolol (racemic), orR-oxprenolol.

FIG. 19 is a graph showing the change in disease progression scored fromscore 1 to score 3 of mice populations that were administered withS-oxprenolol, rilutek, propanolol, oxprenolol (racemic), orR-oxprenolol.

FIG. 20A is a graph showing the change in body weight of micepopulations that were administered with S-oxprenolol, R-oxprenolol, orrilutek. FIG. 20B is a graph showing the change in body weight of malemice populations that were administered with S-oxprenolol, R-oxprenolol,or rilutek. FIG. 20C is a graph showing the change in body weight offemale mice populations that were administered with S-oxprenolol.R-oxprenolol, or rilutek. FIG. 20D is a graph showing the change in leanmass of mice populations that were administered with S-oxprenolol,R-oxprenolol, or rilutek. FIG. 20E is a graph showing the change in leanmass of male mice populations that were administered with S-oxprenolol,R-oxprenolol, or rilutek. FIG. 20F is a graph showing the change in leanmass of female mice populations that were administered withS-oxprenolol. R-oxprenolol, or rilutek. FIG. 20G is a graph showing thechange in fat mass of mice populations that were administered withS-oxprenolol, R-oxprenolol, or rilutek. FIG. 20H is a graph showing thechange in fat mass of male mice populations that were administered withS-oxprenolol, R-oxprenolol, or rilutek. FIG. 20I is a graph showing thechange in fat mass of female mice populations that were administeredwith S-oxprenolol, R-oxprenolol, or rilutek. The sample size in thepopulation is indicated by “n.”

FIG. 21A is a graph showing the heart mass of mice populations that wereadministered with S-oxprenolol, R-oxprenolol, or rilutek at the end ofthe study. FIG. 21B is a graph showing the heart mass of male micepopulations that were administered with S-oxprenolol, R-oxprenolol, orrilutek at the end of the study. FIG. 21C is a graph showing the heartmass of female mice populations that were administered withS-oxprenolol, R-oxprenolol, or rilutek at the end of the study. FIG. 21Dis a graph showing gastrocnemius muscle weight of mice populations thatwere administered with S-oxprenolol, R-oxprenolol, or rilutek at the endof the study. FIG. 21E is a graph showing gastrocnemius muscle weight ofmale mice populations that were administered with S-oxprenolol.R-oxprenolol, or rilutek at the end of the study. FIG. 21F is a graphshowing gastrocnemius muscle weight of female mice populations that wereadministered with S-oxprenolol. R-oxprenolol, or rilutek at the end ofthe study. FIG. 21G is a graph showing tibialis muscle weight of micepopulations that were administered with S-oxprenolol, R-oxprenolol, orrilutek at the end of the study. FIG. 21H is a graph showing tibialismuscle weight of male mice populations that were administered withS-oxprenolol, R-oxprenolol, or rilutek at the end of the study. FIG. 21Iis a graph showing tibialis muscle weight of female mice populationsthat were administered with S-oxprenolol, R-oxprenolol, or rilutek atthe end of the study. The sample size in the population is indicated by“n.”

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides use of an S-enantiomerically enrichedcomposition of a beta blocker for achieving beneficial results inindividuals having amyotrophic lateral sclerosis, such as treatingamyotrophic lateral sclerosis, prolonging survival, preventing lean massloss, improving quality of life, and/or treating muscle wasting. In anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof, the beta blocker or apharmaceutically acceptable salt thereof has one chiral center and thecomposition is enantiomerically enriched for the S-enantiomer. Thus, asused herein. “S-enantiomerically enriched composition of a beta blocker”refers to a beta blocker having one chiral center and the composition isenantiomerically enriched for the S-enantiomer. In some embodiments, thebeta blocker is oxprenolol or a pharmaceutically acceptable saltthereof.

The present invention is based on the surprising finding thatS-oxprenolol significantly improved survival in animals havingamyotrophic lateral sclerosis in an experiment using an amyotrophiclateral sclerosis animal model. Other effects of the compositions wereobserved on preserving lean body mass and preventing body weight loss inthe animals. At least, these effects suggest that S-oxprenolol iseffective in treating amyotrophic lateral sclerosis and prolongingsurvival.

Thus, the present invention, in one aspect, provides methods of treatingamyotrophic lateral sclerosis, prolonging survival, preventing lean massloss, preventing and/or treating muscle wasting, or improving quality oflife in an individual having amyotrophic lateral sclerosis, comprisingadministering to the individual an effective amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof. In some embodiments, the betablocker is oxprenolol or a pharmaceutically acceptable salt thereof.

Also provided are kits, unit dosages, medicines, and articles ofmanufacture that are useful for methods described herein.

DEFINITIONS

The following terms have the following meanings unless otherwiseindicated. Any undefined terms have their art recognized meanings.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results including clinical results. For purposesof this invention, beneficial or desired clinical results include, butare not limited to, one or more of the following: alleviating one ormore symptoms resulting from the disease, diminishing the extent of thedisease, stabilizing the disease (e.g., preventing or delaying theworsening of the disease), preventing or delaying the spread (e.g.,metastasis) of the disease, preventing or delaying the recurrence of thedisease, delay or slowing the progression of the disease, amelioratingthe disease state, providing a remission (partial or total) of thedisease, decreasing the dose of one or more other medications requiredto treat the disease, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival. Alsoencompassed by “treatment” is a reduction of pathological consequence ofamyotrophic lateral sclerosis. The methods of the invention contemplateany one or more of these aspects of treatment.

The term “individual” refers to a mammal and includes, hut is notlimited to, human, bovine, horse, feline, canine, rodent, or primate. Insome embodiments, the individual is a human.

As used herein, an “at risk” individual is an individual who is at riskof developing amyotrophic lateral sclerosis. An individual “at risk” mayor may not have detectable disease, and may or may not have displayeddetectable disease prior to the treatment methods described herein. “Atrisk” denotes that an individual has one or more so-called risk factors,which are measurable parameters that correlate with development ofamyotrophic lateral sclerosis. An individual having one or more of theserisk factors has a higher probability of developing amyotrophic lateralsclerosis than an individual without these risk factor(s).

As used herein, “delaying” the development of a disease means to defer,hinder, slow, retard, stabilize, and/or postpone development of thedisease. This delay can be of varying lengths of time, depending on thehistory of the disease and/or individual being treated. As is evident toone skilled in the art, a sufficient or significant delay can, ineffect, encompass prevention, in that the individual does not developthe disease. A method that “delays” development of a disease is a methodthat reduces probability of disease development in a given time frameand/or reduces the extent of the disease in a given time frame, whencompared to not using the method. Such comparisons are typically basedon clinical studies, using a statistically significant number ofsubjects.

As used herein, by “combination therapy” is meant that a first agent beadministered in conjunction with another agent. “In conjunction with”refers to administration of one treatment modality in addition toanother treatment modality, such as administration of a nanoparticlecomposition described herein in addition to administration of the otheragent to the same individual. As such. “in conjunction with” refers toadministration of one treatment modality before, during, or afterdelivery of the other treatment modality to the individual. Suchcombinations are considered to be part of a single treatment regimen orregime.

The term “effective amount” used herein refers to an amount of acompound or composition sufficient to treat a specified disorder,condition or disease such as ameliorate, palliate, lessen, and/or delayone or more of its symptoms. In reference to amyotrophic lateralsclerosis, an effective amount comprises an amount sufficient to preventor delay other unwanted symptoms associated with amyotrophic lateralsclerosis. In some embodiments, an effective amount is an amountsufficient to delay development. In some embodiments, an effectiveamount is an amount sufficient to prevent or delay recurrence. Aneffective amount can be administered in one or more administrations.

The term “simultaneous administration,” as used herein, means that afirst therapy and second therapy in a combination therapy areadministered with a time separation of no more than about 15 minutes,such as no more than about any of 10, 5, or 1 minutes. When the firstand second therapies are administered simultaneously, the first andsecond therapies may be contained in the same composition (e.g., acomposition comprising both a first and second therapy) or in separatecompositions (e.g., a first therapy in one composition and a secondtherapy is contained in another composition).

As used herein, the term “sequential administration” means that thefirst therapy and second therapy in a combination therapy areadministered with a time separation of more than about 15 minutes, suchas more than about any of 20, 30, 40, 50, 60, or more minutes. Eitherthe first therapy or the second therapy may be administered first. Thefirst and second therapies are contained in separate compositions, whichmay be contained in the same or different packages or kits.

As used herein, the term “concurrent administration” means that theadministration of the first therapy and that of a second therapy in acombination therapy overlap with each other.

As used herein, by “pharmaceutically acceptable” or “pharmacologicallycompatible” is meant a material that is not biologically or otherwiseundesirable, e.g., the material may be incorporated into apharmaceutical composition administered to an individual without causingany significant undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. Pharmaceutically acceptable carriers orexcipients have preferably met the required standards of toxicologicaland manufacturing testing and/or are included on the Inactive IngredientGuide prepared by the U.S. Food and Drug administration.

An “adverse event” or “AE” as used herein refers to any untoward medicaloccurrence in an individual receiving a marketed pharmaceutical productor in an individual who is participating on a clinical trial who isreceiving an investigational or non-investigational pharmaceuticalagent.

The term “isomers” or “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “diastereomers” refers to stereoisomers with two or morecenters of dissymmetry and whose molecules are not mirror images of oneanother.

The term “enantiomers” refers to two stereoisomers of a compound whichare non-superimposable mirror images of one another. An equimolarmixture of two enantiomers is called a “racemic mixture” or a“racemate.”

The term “enantiomerically enriched” means that the racemic mixture(i.e., 50/50 mixture of the enantiomers) has been purified such that oneenantiomer comprises greater than 50% of the total amount of thecompound present. For example, a composition that is enantiomericallyenriched for S-oxprenolol is a composition wherein more than 50% of theoxprenolol is the S-enantiomer of oxprenolol (S-oxprenolol).

The degree of enantiomeric enrichment of a composition can be determinedby “enantiomeric excess.” or ee. “Enantiomeric excess” represents thepercentage of one enantiomer in excess of the other. For instance, acomposition having a 75:25 mixture of S-oxprenolol and R-oxprenolol hasa 75−25=50% ee, while a 50:50 racemic mixture has a 50−50=0% ee. Thevalue of ee will be a number from 0 to 100, 0 being racemic and 100being pure, single enantiomer.

The term “pharmaceutically acceptable salt” means a salt which isacceptable for administration to a subject, such as a mammal (salts withcounterions having acceptable mammalian safety for a given dosageregime). Such salts can be derived from pharmaceutically acceptableinorganic or organic bases and from pharmaceutically acceptableinorganic or organic acids. “Pharmaceutically acceptable salt” refers topharmaceutically acceptable salts of a compound, which salts are derivedfrom a variety of organic and inorganic counter ions well known in theart and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, formate, tartrate, besylate,mesylate, acetate, maleate, oxalate, and the like.

The term “salt thereof” means a compound formed when a proton of an acidis replaced by a cation, such as a metal cation or an organic cation andthe like. Where applicable, the salt is a pharmaceutically acceptablesalt, although this is not required for salts of intermediate compoundsthat are not intended for administration to the subject. By way ofexample, salts of the present compounds include those wherein thecompound is protonated by an inorganic or organic acid to form a cation,with the conjugate base of the inorganic or organic acid as the anioniccomponent of the salt.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of the solute. The solvent can be an organiccompound, an inorganic compound, or a mixture of both. Some examples ofsolvents include, but are not limited to, methanol.N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.When the solvent is water, the solvate formed is a hydrate.

It will be appreciated that the term “or a salt or solvate thereof” isintended to include all permutations of salts and solvates, such as asolvate of a pharmaceutically acceptable salt of a subject compound.

As used herein, “in conjunction with” refers to administration of onetreatment modality in addition to another treatment modality. As such,“in conjunction with” refers to administration of one treatment modalitybefore, during or after administration of the other treatment modalityto the individual.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural reference unless the context clearly indicatesotherwise.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X.”

It is understood that aspects and variations of the invention describedherein include “consisting” and/or “consisting essentially of” aspectsand variations.

Methods of the Present Invention

The present disclosure, in one aspect, provides methods of treatingamyotrophic lateral sclerosis. In some embodiments, there is provided amethod of treating amyotrophic lateral sclerosis in an individual havingamyotrophic lateral sclerosis, comprising administering to theindividual an effective amount of an S-enantiomerically enrichedcomposition of a beta blocker or a pharmaceutically acceptable saltthereof (such as a composition having at least about any one of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or99.9% ee). In some embodiments, the beta blocker is selected from thegroup consisting of acebutolol, atenolol, betaxolol, bisoprolol,carteolol, celeprolol, labetalol, metoprolol, nadolol, nehivolol,oxprenolol, penbutolol, pindolol, propanolol, sotalol, esmolol,carvedilol, timolol, bopindolol, medroxalol, bucindolol, levobunolol,metipranolol, celiprolol and propafenone or a pharmaceuticallyacceptable salt thereof. In some embodiments, the beta blocker isoxprenolol or a pharmaceutically acceptable salt thereof. In someembodiments, the composition comprises an enantiomeric excess of atleast about 10% (such as at least about any one of 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9%) of S-oxprenolol.In some embodiments, there is provided a method of treating amyotrophiclateral sclerosis in an individual having amyotrophic lateral sclerosis,comprising administering to the individual an effective amount of acomposition comprising oxprenolol or a pharmaceutically acceptable saltthereof, wherein the composition comprises an enantiomeric excess of atleast about 99% (for example at least about 99.9%) of S-oxprenolol. Insome embodiments, there is provided a method of treating amyotrophiclateral sclerosis in an individual having amyotrophic lateral sclerosis,comprising administering (such as orally administering) to theindividual an effective amount of a composition comprising oxprenolol ora pharmaceutically acceptable salt thereof, wherein the composition isenantiomerically enriched for S-oxprenolol (for example comprises anenantiomeric excess of at least about 99% of S-oxprenolol), wherein theamount of S-oxprenolol in the composition is about 50 mg to about 160 mg(such as about 80 to about 160 mg, for example about 100 mg to about 160mg).

In some embodiments, there is provided a method of prolonging survivalof an individual having amyotrophic lateral sclerosis, comprisingadministering to the individual an effective amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (such as a composition havingat least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, the betablocker is selected from the group consisting of acebutolol, atenolol,betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol,nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol,sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol,bucindolol, levobunolol, metipranolol, celiprolol and propafenone. Insome embodiments, the beta blocker is oxprenolol or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprisesan enantiomeric excess of at least about 10% (such as at least about anyone of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%,or 99.9%) of S-oxprenolol. In some embodiments, there is provided amethod of prolonging survival in an individual having amyotrophiclateral sclerosis, comprising administering to the individual aneffective amount of a composition comprising oxprenolol or apharmaceutically acceptable salt thereof, wherein the compositioncomprises an enantiomeric excess of at least about 99% (for example atleast about 99.9%) of S-oxprenolol. In some embodiments, there isprovided a method of prolonging survival of an individual havingamyotrophic lateral sclerosis, comprising administering (such as orallyadministering) to the individual an effective amount of a compositioncomprising oxprenolol or a pharmaceutically acceptable salt thereof,wherein the composition is enantiomerically enriched for S-oxprenolol(for example comprises an enantiomeric excess of at least about 99% ofS-oxprenolol), wherein the amount of S-oxprenolol in the composition isabout 50 mg to about 160 mg (such as about 80 to about 160 mg, forexample about 100 mg to about 160 mg). In some embodiments, the methodprolongs the survival of the individual by at least any of 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 18, or 24 months.

In some embodiments, there is provided a method of prolongingprogression-free survival in an individual with amyotrophic lateralsclerosis, comprising administering to the individual an effectiveamount of an S-enantiomerically enriched composition of a beta blockeror a pharmaceutically acceptable salt thereof (such as a compositionhaving at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, 95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, thebeta blocker is selected from the group consisting of acebutolol,atenolol, betaxolol, bisoprolol, carteolol, celeprolol, labetalol,metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol,propanolol, sotalol, esmolol, carvedilol, timolol, bopindolol,medroxalol, bucindolol, levobunolol, metipranolol, celiprolol andpropafenone. In some embodiments, the beta blocker is oxprenolol or apharmaceutically acceptable salt thereof. In some embodiments, thecomposition comprises an enantiomeric excess of at least about 10% (suchas at least about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9%) of S-oxprenolol. In some embodiments,there is provided a method of prolonging progression-free survival in anindividual with amyotrophic lateral sclerosis, comprising administeringto the individual an effective amount of a composition comprisingoxprenolol or a pharmaceutically acceptable salt thereof, wherein thecomposition comprises an enantiomeric excess of at least about 99% (forexample at least about 99.9%) of S-oxprenolol. In some embodiments,there is provided a method of prolonging progression-free survival in anindividual with amyotrophic lateral sclerosis, comprising administering(such as orally administering) to the individual an effective amount ofa composition comprising oxprenolol or a pharmaceutically acceptablesalt thereof, wherein the composition is enantiomerically enriched forS-oxprenolol (for example comprises an enantiomeric excess of at leastabout 99% of S-oxprenolol), wherein the amount of S-oxprenolol in thecomposition is about 50 mg to about 160 mg (such as about 80 to about160 mg, for example about 100 mg to about 160 mg).

In some embodiments, there is provided a method of alleviating one ormore symptoms associated with amyotrophic lateral sclerosis, comprisingadministering to the individual an effective amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (such as a composition havingat least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, the betablocker is selected from the group consisting of acebutolol, atenolol,betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol,nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol,sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol,bucindolol, levobunolol, metipranolol, celiprolol and propafenone. Insome embodiments, the beta blocker is oxprenolol or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprisesan enantiomeric excess of at least about 10% (such as at least about anyone of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%,or 99.9%) of S-oxprenolol. In some embodiments, there is provided amethod of alleviating one or more symptoms associated with amyotrophiclateral sclerosis, comprising administering to the individual aneffective amount of a composition comprising oxprenolol or apharmaceutically acceptable salt thereof, wherein the compositioncomprises an enantiomeric excess of at least about 99% (for example atleast about 99.9%) of S-oxprenolol. In some embodiments, there isprovided a method of alleviating one or more symptoms associated withamyotrophic lateral sclerosis, comprising administering (such as orallyadministering) to the individual an effective amount of a compositioncomprising oxprenolol or a pharmaceutically acceptable salt thereof,wherein the composition is enantiomerically enriched for S-oxprenolol(for example comprises an enantiomeric excess of at least about 99% ofS-oxprenolol), wherein the amount of S-oxprenolol in the composition isabout 50 mg to about 160 mg (such as about 80 to about 160 mg, forexample about 100 mg to about 160 mg).

In some embodiments, there is provided a method of delaying thedevelopment of amyotrophic lateral sclerosis in an individual havingamyotrophic lateral sclerosis, comprising administering to theindividual an effective amount of an S-enantiomerically enrichedcomposition of a beta blocker or a pharmaceutically acceptable saltthereof (such as a composition having at least about any one of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or99.9% ee). In some embodiments, the beta blocker is oxprenolol or apharmaceutically acceptable salt thereof. In some embodiments, the betablocker is selected from the group consisting of acebutolol, atenolol,betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol,nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol,sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol,bucindolol, levobunolol, metipranolol, celiprolol and propafenone. Insome embodiments, the composition comprises oxprenolol or apharmaceutically acceptable salt thereof. In some embodiments, thecomposition comprises oxprenolol or a pharmaceutically acceptable saltthereof, wherein the composition is enantiomerically enriched forS-oxprenolol. In some embodiments, the composition comprises anenantiomeric excess of at least about 10% (such as at least about anyone of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%,or 99.9%) of S-oxprenolol. In some embodiments, there is provided amethod of delaying the development of amyotrophic lateral sclerosis inan individual having amyotrophic lateral sclerosis, comprisingadministering to the individual an effective amount of a compositioncomprising oxprenolol or a pharmaceutically acceptable salt thereof,wherein the composition comprises an enantiomeric excess of at leastabout 99% (for example at least about 99.9%) of S-oxprenolol. In someembodiments, there is provided a method of delaying the development ofamyotrophic lateral sclerosis in an individual having amyotrophiclateral sclerosis, comprising administering (such as orallyadministering) to the individual an effective amount of a compositioncomprising oxprenolol or a pharmaceutically acceptable salt thereof,wherein the composition is enantiomerically enriched for S-oxprenolol(for example comprises an enantiomeric excess of at least about 99% ofS-oxprenolol), wherein the amount of S-oxprenolol in the composition isabout 50 mg to about 160 mg (such as about 80 to about 160 mg, forexample about 100 mg to about 160 mg). In some embodiments, the methodprolongs the survival of the individual by at least any of 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 18, or 24 months.

In some embodiments, there is provided a method of preventing loss oflean body mass in an individual having amyotrophic lateral sclerosis,comprising administering to the individual an effective amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (such as a composition havingat least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, there isprovided a method of treating loss of lean body mass in an individualhaving amyotrophic lateral sclerosis, comprising administering to theindividual an effective amount of an S-enantiomerically enrichedcomposition of a beta blocker or a pharmaceutically acceptable saltthereof (such as a composition having at least about any one of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or99.9% ee). In some embodiments, the method of treating loss of lean bodymass is reversing muscle wasting or increasing muscle weight. In someembodiments, the beta blocker is selected from the group consisting ofacebutolol, atenolol, betaxolol, bisoprolol, carteolol, celeprolol,labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol,pindolol, propanolol, sotalol, esmolol, carvedilol, timolol, bopindolol,medroxalol, bucindolol, levobunolol, metipranolol, celiprolol andpropafenone. In some embodiments, the beta blocker is oxprenolol or apharmaceutically acceptable salt thereof. In some embodiments, thecomposition comprises an enantiomeric excess of at least about 10% (suchas at least about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9%) of S-oxprenolol. In some embodiments,there is provided a method of preventing loss of lean body mass in anindividual having amyotrophic lateral sclerosis, comprisingadministering to the individual an effective amount of a compositioncomprising oxprenolol or a pharmaceutically acceptable salt thereof,wherein the composition comprises an enantiomeric excess of at leastabout 99% (for example at least about 99.9%) of S-oxprenolol. In someembodiments, there is provided a method of preventing loss of lean bodymass in an individual having amyotrophic lateral sclerosis, comprisingadministering (such as orally administering) to the individual aneffective amount of a composition comprising oxprenolol or apharmaceutically acceptable salt thereof, wherein the composition isenantiomerically enriched for S-oxprenolol (for example comprises anenantiomeric excess of at least about 99% of S-oxprenolol), wherein theamount of S-oxprenolol in the composition is about 50 mg to about 160 mg(such as about 80 to about 160 mg, for example about 100 mg to about 160mg). In some embodiments, the loss of lean body mass of the individualis no more than about 10% (for example no more than about any of 10%,9%, 8%, 7%, 6%, or 5%) of the total lean body mass. In some embodiments,the loss of lean body mass is evaluated over a time period of about 1month to 2 years (for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months).

In some embodiments, there is provided a method of treating musclewasting in an individual having amyotrophic lateral sclerosis,comprising administering to the individual an effective amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (such as a composition havingat least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, the betablocker is selected from the group consisting of acebutolol, atenolol,betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol,nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol,sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol,bucindolol, levobunolol, metipranolol, celiprolol and propafenone. Insome embodiments, the beta blocker is oxprenolol or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprisesan enantiomeric excess of at least about 100 (such as at least about anyone of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%,or 99.9%) of S-oxprenolol. In some embodiments, there is provided amethod of treating muscle wasting in an individual having amyotrophiclateral sclerosis, comprising administering to the individual aneffective amount of a composition comprising oxprenolol or apharmaceutically acceptable salt thereof, wherein the compositioncomprises an enantiomeric excess of at least about 99% (for example atleast about 99.9%) of S-oxprenolol. In some embodiments, there isprovided a method of treating muscle wasting in an individual havingamyotrophic lateral sclerosis, comprising administering (such as orallyadministering) to the individual an effective amount of a compositioncomprising oxprenolol or a pharmaceutically acceptable salt thereof,wherein the composition is enantiomerically enriched for S-oxprenolol(for example comprises an enantiomeric excess of at least about 99% ofS-oxprenolol), wherein the amount of S-oxprenolol in the composition isabout 50 mg to about 160 mg (such as about 80 to about 160 mg, forexample about 100 mg to about 160 mg). In some embodiments, the musclewasting of the individual is no more than about 10% (for example no morethan about any of 10%, 9%, 8%, 7%, 6%, or 5%) of the total body weight.In some embodiments, the muscle wasting is evaluated over a time periodof about 1 month to 2 years (for example, about 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24months). In some embodiments, the method leads to a reduction of musclewasting, i.e., a slow-down of muscle loss in the individual. In someembodiments, the method leads to a reversal of muscle wasting, i.e., anincrease in muscle weight in the individual.

In some embodiments, there is provided a method of improving quality oflife of an individual having amyotrophic lateral sclerosis, comprisingadministering to the individual an effective amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (such as a composition havingat least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, the betablocker is selected from the group consisting of acebutolol, atenolol,betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol,nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol,sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol,bucindolol, levobunolol, metipranolol, celiprolol and propafenone. Insome embodiments, the beta blocker is oxprenolol or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprisesan enantiomeric excess of at least about 10% (such as at least about anyone of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%,or 99.9%) of S-oxprenolol. In some embodiments, there is provided amethod of improving quality of life of an individual having amyotrophiclateral sclerosis, comprising administering to the individual aneffective amount of a composition comprising oxprenolol or apharmaceutically acceptable salt thereof, wherein the compositioncomprises an enantiomeric excess of at least about 99% (for example atleast about 99.9%) of S-oxprenolol. In some embodiments, there isprovided a method of improving quality of life of an individual havingamyotrophic lateral sclerosis, comprising administering (such as orallyadministering) to the individual an effective amount of a compositioncomprising oxprenolol or a pharmaceutically acceptable salt thereof,wherein the composition is enantiomerically enriched for S-oxprenolol(for example comprises an enantiomeric excess of at least about 99% ofS-oxprenolol), wherein the amount of S-oxprenolol in the composition isabout 50 mg to about 160 mg (such as about 80 to about 160 mg, forexample about 100 mg to about 160 mg). Improvement of quality of lifecan be assessed, for example, by food intake, locomotive activity,improvement in fatigue or dyspnea or global patient assessment scores,in short physical performance battery scores, in standard clinicalassessment of functional performance, muscle strength, gait speed, legstrength and hand grip strength, 6-minute corridor walk test, stairclimbing power, ability to tolerate courses of chemotherapy and othertests or instruments or questionnaires assessing patient quality oflife.

In some embodiments, there is provided a method of increasing foodintake of an individual having amyotrophic lateral sclerosis, comprisingadministering to the individual an effective amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (such as a composition havingat least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, the betablocker is selected from the group consisting of acebutolol, atenolol,betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol,nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol,sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol,bucindolol, levobunolol, metipranolol, celiprolol and propafenone. Insome embodiments, the beta blocker is oxprenolol or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprisesan enantiomeric excess of at least about 10% (such as at least about anyone of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%,or 99.9%) of S-oxprenolol. In some embodiments, there is provided amethod of increasing food intake of an individual having amyotrophiclateral sclerosis, comprising administering to the individual aneffective amount of a composition comprising oxprenolol or apharmaceutically acceptable salt thereof, wherein the compositioncomprises an enantiomeric excess of at least about 99% (for example atleast about 99.9%) of S-oxprenolol. In some embodiments, there isprovided a method of increasing food intake of an individual havingamyotrophic lateral sclerosis, comprising administering (such as orallyadministering) to the individual an effective amount of a compositioncomprising oxprenolol or a pharmaceutically acceptable salt thereof,wherein the composition is enantiomerically enriched for S-oxprenolol(for example comprises an enantiomeric excess of at least about 99% ofS-oxprenolol), wherein the amount of S-oxprenolol in the composition isabout 50 mg to about 160 mg (such as about 80 to about 160 mg, forexample about 100 mg to about 160 mg).

In some embodiments, there is provided a method of increasing locomotiveactivity of an individual having amyotrophic lateral sclerosis,comprising administering to the individual an effective amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (such as a composition havingat least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, the betablocker is selected from the group consisting of acebutolol, atenolol,betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol,nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol,sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol,bucindolol, levobunolol, metipranolol, celiprolol and propafenone. Insome embodiments, the beta blocker is oxprenolol or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprisesan enantiomeric excess of at least about 10% (such as at least about anyone of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%,or 99.9%) of S-oxprenolol. In some embodiments, there is provided amethod of increasing locomotive activity of an individual havingamyotrophic lateral sclerosis, comprising administering to theindividual an effective amount of a composition comprising oxprenolol ora pharmaceutically acceptable salt thereof, wherein the compositioncomprises an enantiomeric excess of at least about 99% (for example atleast about 99.9%) of S-oxprenolol. In some embodiments, there isprovided a method of increasing locomotive activity of an individualhaving amyotrophic lateral sclerosis, comprising administering (such asorally administering) to the individual an effective amount of acomposition comprising oxprenolol or a pharmaceutically acceptable saltthereof, wherein the composition is enantiomerically enriched forS-oxprenolol (for example comprises an enantiomeric excess of at leastabout 99% of S-oxprenolol), wherein the amount of S-oxprenolol in thecomposition is about 50 mg to about 160 mg (such as about 80 to about160 mg, for example about 100 mg to about 160 mg).

In some embodiments, there is provided a method of improving fatigue ordyspnea in an individual having amyotrophic lateral sclerosis,comprising administering to the individual an effective amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (such as a composition havingat least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, the betablocker is selected from the group consisting of acebutolol, atenolol,betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol,nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol,sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol,bucindolol, levobunolol, metipranolol, celiprolol and propafenone. Insome embodiments, the beta blocker is oxprenolol or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprisesan enantiomeric excess of at least about 10% (such as at least about anyone of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%,or 99.9%) of S-oxprenolol. In some embodiments, there is provided amethod of improving fatigue or dyspnea in an individual havingamyotrophic lateral sclerosis, comprising administering to theindividual an effective amount of a composition comprising oxprenolol ora pharmaceutically acceptable salt thereof, wherein the compositioncomprises an enantiomeric excess of at least about 99% (for example atleast about 99.9%) of S-oxprenolol. In some embodiments, there isprovided a method of improving fatigue or dyspnea in an individualhaving amyotrophic lateral sclerosis, comprising administering (such asorally administering) to the individual an effective amount of acomposition comprising oxprenolol or a pharmaceutically acceptable saltthereof, wherein the composition is enantiomerically enriched forS-oxprenolol (for example comprises an enantiomeric excess of at leastabout 99% of S-oxprenolol), wherein the amount of S-oxprenolol in thecomposition is about 50 mg to about 160 mg (such as about 80 to about160 mg, for example about 100 mg to about 160 mg).

In some embodiments, there is provided a method of preventing bodyweight loss of an individual having amyotrophic lateral sclerosis,comprising administering to the individual an effective amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (such as a composition havingat least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, the betablocker is selected from the group consisting of acebutolol, atenolol,betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol,nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol,sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol,bucindolol, levobunolol, metipranolol, celiprolol and propafenone. Insome embodiments, the beta blocker is oxprenolol or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprisesan enantiomeric excess of at least about 10% (such as at least about anyone of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%,or 99.9%) of S-oxprenolol. In some embodiments, there is provided amethod of preventing body weight loss in an individual havingamyotrophic lateral sclerosis, comprising administering to theindividual an effective amount of a composition comprising oxprenolol ora pharmaceutically acceptable salt thereof, wherein the compositioncomprises an enantiomeric excess of at least about 99% (for example atleast about 99.9%) of S-oxprenolol. In some embodiments, there isprovided a method of preventing body weight loss of an individual havingamyotrophic lateral sclerosis, comprising administering (such as orallyadministering) to the individual an effective amount of a compositioncomprising oxprenolol or a pharmaceutically acceptable salt thereof,wherein the composition is enantiomerically enriched for S-oxprenolol(for example comprises an enantiomeric excess of at least about 99% ofS-oxprenolol), wherein the amount of S-oxprenolol in the composition isabout 50 mg to about 160 mg (such as about 80 to about 160 mg, forexample about 100 mg to about 160 mg). In some embodiments, the bodyweight loss of the individual is no more than about 20% (for example nomore than about any of 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or5%) of the total body weight. In some embodiments, the body weight lossis evaluated over a time period of about 1 month to 2 years (forexample, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, or 24 months).

In some embodiments, there is provided a method of preventing loss ofbody fat in an individual having amyotrophic lateral sclerosis,comprising administering to the individual an effective amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (such as a composition havingat least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, the betablocker is selected from the group consisting of acebutolol, atenolol,betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol,nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol,sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol,bucindolol, levobunolol, metipranolol, celiprolol and propafenone. Insome embodiments, the beta blocker is oxprenolol or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprisesan enantiomeric excess of at least about 10% (such as at least about anyone of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%,or 99.9%) of S-oxprenolol. In some embodiments, there is provided amethod of preventing loss of body fat in an individual havingamyotrophic lateral sclerosis, comprising administering to theindividual an effective amount of a composition comprising oxprenolol ora pharmaceutically acceptable salt thereof, wherein the compositioncomprises an enantiomeric excess of at least about 99% (for example atleast about 99.9%) of S-oxprenolol. In some embodiments, there isprovided a method of preventing loss of body fat in an individual havingamyotrophic lateral sclerosis, comprising administering (such as orallyadministering) to the individual an effective amount of a compositioncomprising oxprenolol or a pharmaceutically acceptable salt thereof,wherein the composition is enantiomerically enriched for S-oxprenolol(for example comprises an enantiomeric excess of at least about 99% ofS-oxprenolol), wherein the amount of S-oxprenolol in the composition isabout 50 mg to about 160 mg (such as about 80 to about 160 mg, forexample about 100 mg to about 160 mg). In some embodiments, the loss ofbody fat of the individual is no more than about 10% (for example nomore than about any of 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or5%) of the total body fat. In some embodiments, the loss of body fat isevaluated over a time period of about 1 month to 2 years (for example,about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, or 24 months).

In some embodiments, there is provided a method of providingcardioprotective effects in an individual having amyotrophic lateralsclerosis, comprising administering to the individual an effectiveamount of an S-enantiomerically enriched composition of a beta blockeror a pharmaceutically acceptable salt thereof (such as a compositionhaving at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, 95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, thereis provided a method of preventing wasting of a heart muscle in anindividual having amyotrophic lateral sclerosis, comprisingadministering to the individual an effective amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (such as a composition havingat least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, the betablocker is selected from the group consisting of acebutolol, atenolol,betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol,nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol,sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol,bucindolol, levobunolol, metipranolol, celiprolol and propafenone. Insome embodiments, the beta blocker is oxprenolol or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprisesan enantiomeric excess of at least about 10% (such as at least about anyone of 20%, 30%, 40%, 50%, 60%, 70%, 800%, 900%, 95%, 96%, 97%, 98%,99%, or 99.9%) of S-oxprenolol. In some embodiments, there is provided amethod of providing cardioprotective effects in an individual havingamyotrophic lateral sclerosis, comprising administering to theindividual an effective amount of a composition comprising oxprenolol ora pharmaceutically acceptable salt thereof, wherein the compositioncomprises an enantiomeric excess of at least about 99% (for example atleast about 99.9%) of S-oxprenolol. In some embodiments, there isprovided a method of preventing wasting of a heart muscle in anindividual having amyotrophic lateral sclerosis, comprisingadministering to the individual an effective amount of a compositioncomprising oxprenolol or a pharmaceutically acceptable salt thereof,wherein the composition comprises an enantiomeric excess of at leastabout 99% (for example at least about 99.9%) of S-oxprenolol. In someembodiments, there is provided a method of providing cardioprotectiveeffects in an individual having amyotrophic lateral sclerosis,comprising administering (such as orally administering) to theindividual an effective amount of a composition comprising oxprenolol ora pharmaceutically acceptable salt thereof, wherein the composition isenantiomerically enriched for S-oxprenolol (for example comprises anenantiomeric excess of at least about 99% of S-oxprenolol), wherein theamount of S-oxprenolol in the composition is about 50 mg to about 160 mg(such as about 80 to about 160 mg, for example about 100 mg to about 160mg). In some embodiments, there is provided a method of preventingwasting of a heart muscle in an individual having amyotrophic lateralsclerosis, comprising administering (such as orally administering) tothe individual an effective amount of a composition comprisingoxprenolol or a pharmaceutically acceptable salt thereof, wherein thecomposition is enantiomerically enriched for S-oxprenolol (for examplecomprises an enantiomeric excess of at least about 99% of S-oxprenolol),wherein the amount of S-oxprenolol in the composition is about 50 mg toabout 160 mg (such as about 80 to about 160 mg, for example about 100 mgto about 160 mg). Cardioprotective effects include one or more of thefollowing: preventing and treating atrial fibrillation and ventricularfibrillation, improving arrhythmias, improving diastolic function of aheart, and preventing and treating fibrosis of a heart. The methodsdescribed herein are therefore useful for any one or more of thesecardioprotective effects.

In some embodiments, there is provided a method of preventing suddendeath and/or cardiovascular death in an individual having amyotrophiclateral sclerosis, comprising administering to the individual aneffective amount of an S-enantiomerically enriched composition of a betablocker or a pharmaceutically acceptable salt thereof (such as acomposition having at least about any one of 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9% ee). In someembodiments, the beta blocker is selected from the group consisting ofacebutolol, atenolol, betaxolol, bisoprolol, carteolol, celeprolol,labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol,pindolol, propanolol, sotalol, esmolol, carvedilol, timolol, bopindolol,medroxalol, bucindolol, levobunolol, metipranolol, celiprolol andpropafenone. In some embodiments, the beta blocker is oxprenolol or apharmaceutically acceptable salt thereof. In some embodiments, thecomposition comprises an enantiomeric excess of at least about 10% (suchas at least about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, 96%, 97%, 98%, 99%, or 99.9%) of S-oxprenolol. In some embodiments,there is provided a method of preventing sudden death and/orcardiovascular death in an individual having amyotrophic lateralsclerosis, comprising administering to the individual an effectiveamount of a composition comprising oxprenolol or a pharmaceuticallyacceptable salt thereof, wherein the composition comprises anenantiomeric excess of at least about 99% (for example at least about99.9%) of S-oxprenolol. In some embodiments, there is provided a methodof preventing sudden death and/or cardiovascular death in an individualhaving amyotrophic lateral sclerosis, comprising administering (such asorally administering) to the individual an effective amount of acomposition comprising oxprenolol or a pharmaceutically acceptable saltthereof, wherein the composition is enantiomerically enriched forS-oxprenolol (for example comprises an enantiomeric excess of at leastabout 99% of S-oxprenolol), wherein the amount of S-oxprenolol in thecomposition is about 50 mg to about 160 mg (such as about 80 to about160 mg, for example about 100 mg to about 160 mg).

The methods described herein may also be useful for any one or more ofthe following: 1) preventing loss of skeletal muscle associated withamyotrophic lateral sclerosis; 2) treating muscle weakness associatedwith amyotrophic lateral sclerosis; 3) strengthening skeletal muscle inan individual having amyotrophic lateral sclerosis; 4) treatment ofmuscle wasting associated with amyotrophic lateral sclerosis; 5)treating dyspnea associated with muscle changes in amyotrophic lateralsclerosis; and 6) improving fatigue resistance of muscle in amyotrophiclateral sclerosis. Skeletal muscle includes, but is not limited to,gastrocnemius muscle, tibialis muscle, soleus muscle, and extensordigitorum longus (EDL) muscle, quadriceps, hamstrings, postural muscles,hand muscles, triceps, biceps, masseter and other jaw muscles, andintercostal and other respiratory muscles. The present applicationencompasses any of these methods.

In some embodiments, the individual has been diagnosed with or issuspected of having amyotrophic lateral sclerosis. In some embodiments,the individual exhibits one or more symptoms associated with amyotrophiclateral sclerosis. In some embodiments, the individual is a human. Insome embodiments, the individual is at least about any of 35, 40, 45,50, 55, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, theindividual is a male. In some embodiments, the individual is a female.In some embodiments, the individual has been previously treated foramyotrophic lateral sclerosis. In some embodiments, the individual hasnot previously been treated for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis covers a spectrum of neurodegenerativesyndromes characterized by progressive muscular paralysis reflectingdegeneration of motor neurons in the brain and spinal cord. It is adebilitating disease with varied etiology characterized by rapidlyprogressive weakness, muscle atrophy and fasciculations musclespasticity, difficulty speaking (dysarthria), difficulty swallowing(dysphagia), and difficulty breathing (dyspnea).

Amyotrophic lateral sclerosis can be diagnosed by observation ofsymptoms and signs. An individual may receive neurologic examinations atregular intervals to see whether symptoms are getting worse. Symptomsmay include muscle weakness, muscle atrophy, hyperreflexia (overactivereflexes, including twitching and spastic movement), and spasticity(tightening and contraction of muscles, muscle stiffening). Tests can berun to obtain definitive information to diagnose ALS or rule outdiseases other than ALS. Such tests include electromyography (EMG),nerve conduction velocity (NCV) test, magnetic resonance imaging (MRI),spinal tap, x-rays, myelogram of the cervical spine, and muscle and/ornerve biopsy.

In some embodiments, the individual has early stage amyotrophic lateralsclerosis. In some embodiments, the individual has middle stageamyotrophic lateral sclerosis. In some embodiments, the individual haslate stage amyotrophic lateral sclerosis.

In early stage ALS, the individual can have any of the followingsymptoms.

Muscles Physical effects Symptoms may be limited to a single region ofthe body. Mild symptoms may affect more than one region. Musclescharacterized by: May experience symptoms such as: Weak and soft orstiff, tight and spastic Fatigue Cramping and twitching Poor balanceAtrophy (loss of muscle mass) Slurred words Weak grip Tripping whenwalking

In middle stage ALS, the individual can have any of the followingsymptoms.

Muscles Physical effects Symptoms become more Unused muscles may causecontractures - widespread. Some muscles joints become rigid, painful andmay be are paralyzed, while others deformed. As a result of weakmuscles, an are weakened or unaffected. individual with ALS may:Twitching may continue. Require help to stand Have difficulty eating andswallowing, causing choking Have difficulty breathing, especially lyingdown Some people with ALS experience bouts of uncontrolled andinappropriate laughing or crying (called pseudobulbar affect or PBA).

In late stage ALS, the individual can have any of the followingsymptoms.

Muscles. Physical effects Most voluntary muscles Most people in the latestages of ALS have are paralyzed. The ability to severely limitedmobility and are unable to move air in and out of the care for their ownneeds. lungs is severely Fatigue compromised. Fuzzy thinking HeadachesSusceptibility to pneumonia Speech may no longer be possible Eating anddrinking by mouth may no longer be possible

As used herein. “amyotrophic lateral sclerosis” or “ALS” includes thespectrum of neurodegenerative syndromes known under the names ofClassical (Charcot's) ALS, Lou Gehrig's disease, motor neuron disease(MND), progressive bulbar palsy (PBP), progressive muscular atrophy(PMA), primary lateral sclerosis (PLS), bulbar onset ALS, spinal onsetALS and ALS with multi-system involvement (Wijesekera L C and Leigh P N,Amyotrophic lateral sclerosis. Orphanet Journal of Rare Disease 2009,4:3). Types of ALS include sporadic ALS, familial ALS, Western PacificALS, Juvenile ALS, and Hirayama Disease.

Types of ALS include sporadic ALS, familial ALS, and variants, includingWestern Pacific ALS. Juvenile ALS, and Hirayama Disease. The presentdisclosure provides a method for treating ALS, including sporadic ALS,familial ALS, and variants, including Western Pacific ALS. Juvenile ALS,and Hirayama Disease.

Approximately 10% of cases of ALS are familial. The remaining 90% aresporadic and though to be multifactorial, with both environmental andgenetic components contributing to disease susceptibility. The geneticsof both FALS and SALS is complex. About 20% of cases with autosomaldominant FALS and 2% of patients with SALS show mutations in thecopper/zinc superoxide dismutase (SOD1) gene on chromosome 21. Mutationsin the gene are thought to cause disease through a toxic gain offunction rather than causing impairment of the antioxidant function ofthe SOD 1 enzyme. Although genes different from other than SOD1 havebeen associated with familial ALS, including alsin (ALS2), senataxin(ALS4) or Angiogenin, the genetic defect remains to be identified in themajority of cases.

Sporadic and familial ALS (SALS and FALS, respectively) are clinicallyand pathologically similar, suggesting a common pathogenesis. Both formsproduce similar pathological hallmarks, including progressive muscleweakness, atrophy, and spasticity, each of which reflects thedegeneration and death of upper and lower motor neurons. Denervation ofthe respiratory muscles and diaphragm is generally the fatal event. Incurrent medical practice, the terms “bulbar onset ALS” and “spinal onsetALS” have replaced the terms PBP and Charchot's ALS. Approximately twothirds of patients with typical ALS have a spinal form of the disease(limb onset) and present symptoms related to focal muscle weakness andwasting, where the symptoms may start either distally or proximally inthe upper and lower limbs. Gradually, spasticity may develop in theweakened atrophic limbs, affecting manual dexterity and gait. Patientswith bulbar onset ALS usually present with dysarthria and dysphagia forsolid or liquids, and limbs symptoms can develop almost simultaneouslywith bulbar symptoms, and in the vast majority of cases will occurwithin 1-2 years. Paralysis is progressive and leads to death due torespiratory failure within 2-3 years for bulbar onset cases and 3-5years for limb onset ALS cases.

Western Pacific ALS is a unique neurological disease initiallyidentified among the Chamorro people of Guam and is characterized by acombination of symptoms including stooped posture, a blankexpressionless face, dementia, slow shuffling movement, a resting tremorthat stops upon deliberate action, slow movements, and muscle atrophythat results in muscles dipping down in the hand. Some patients haveParkinsonism features combined with dementia (Parkinsonism DementiaComplex, PDC). In still others, only dementia is observed.Neuropathologically, all clinical forms of the disease result in aspecific feature, neurofibrillary tangles, found in the cortex and inthe spinal cord. Because the disease has aspects that resembleamyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) andAlzheimer's disease (AD), this disease is known as Western Pacific ALSor amyotrophic lateral sclerosis-Parkinsonism dementia complex of Guam(ALS-PDC) and is also known as lytico-bodig.

Juvenile ALS is an adolescent motor neuron disease that is clinicallyindistinguishable from ALS. Onset is between ages of twelve and sixteenyears and occurs below the age of 25 years.

In Hirayama Disease, there is localized atrophy of one arm associatedwith increased reflexes implicating the presence of upper and lowermotor neuron damage. However, Hirayama Disease involves a problem at thejunction between the cervical spine and the skull where there ispressure on the cervical spinal cord. In order to detect HirayamaDisease, an MRI of the neck needs to be performed in different positionsincluding neck flexion and extension.

Other syndromes related to the ALS spectrum of disorders includeprogressive bulbar palsy (PBP), progressive muscular atrophy (PMA),primary lateral sclerosis (PLS) and ALS with multi-system involvement.The present disclosure provides a method for treating a syndrome relatedto the ALS spectrum of disorders, such as progressive bulbar palsy(PBP), progressive muscular atrophy (PMA), primary lateral sclerosis(PLS), or ALS with multi-system involvement.

Progressive bulbar palsy (PBP) is a motor neuron disease, in which thenerves supplying the bulbar muscles are attacked. PBP is characterizedby the degeneration of motor neurons in the cerebral cortex, spinalcord, brain stem, and pyramidal tracts. Progressive bulbar palsysymptoms can include progressive difficulty with chewing, talking, andswallowing. Patients can also exhibit reduced gag reflexes, weak palatalmovements, fasciculations, and weak movement of the facial muscles andtongue. In advanced cases of PBP, the patient may be unable to protrudetheir tongue or manipulate food in their mouth.

Progressive muscular atrophy (PMA, also Duchenne-Aran muscular atrophyor Duchenne-Aran disease) is motor neuron disease which affects thelower motor neurons. Symptoms of PMA include atrophy, fasciculation, andmuscle weakness. Some patients have symptoms restricted to the arms orlegs.

Primary lateral sclerosis (PLS) is a neuromuscular disease characterizedby progressive muscle weakness in the voluntary muscles. PLS affectsupper motor neurons. Symptoms include difficulty with balance andweakness and stiffness in the legs. Other common symptoms are spasticity(involuntary muscle contraction due to the stretching of muscle). Theremay also be difficulty in breathing in the later stages of the disease,causing those patients who develop ventilatory failure. Hyperreflexia isanother feature of PLS as seen in patients presenting with theBabinski's sign. Some people present with emotional lability and bladderurgency, and occasionally people with PLS experience mild cognitivechanges detectable on neuropsychological testing, particularly onmeasures of executive function.

In some embodiments, the benefits of administering the compositions toalleviate the symptoms or treat ALS can be evaluated by the followingtests: a reduction in the rate of decrease in the ALSFRS-R score, theManual Muscle Testing (MMT) score, the Slow Vital Capacity (VC) percentpredicted value, the ALS-Specific Quality of Life (ALSSQoL) score, andEuroQol-5 Dimensions (EQ-5D) Health Outcomes Scale score. Anothersuitable test for evaluation includes a reduction in the rate ofincrease in the Zarit Burden Interview (ZBI) score. Another suitabletest for evaluation is the use of electrical impedance myography as abiomarker (Rutkove et al., Amyotroph Lateral Scler. 2012 September;13(5):439-4). In some embodiments, the rate of decrease in, or thesymptom measured by, the ALSFRS-R score is reduced by at least 15% ascompared to an individual with ALS who is not administered S-oxprenolol.

Beta Blockers

The methods described herein comprise administration of compositionscomprising beta blockers. Beta blockers, which are used to treathypertension, can be used for preventing the onset of amyotrophiclateral sclerosis and for treating amyotrophic lateral sclerosis. Forexample, the use of a beta blocker in an individual with ALS has shownthat the individual has prolonged survival compared to an individualwith ALS that did not receive a beta blocker. Other benefits of the useof a beta blocker include preservation of lean body mass and preventionof body weight loss. These effects suggest that beta blockers can beused to treat ALS, delay the development of ALS, alleviate the symptomsof ALS, and improve the quality of life for ALS patients.

In some embodiments, the beta blocker has intrinsic sympathomimeticactivity (ISA). In some embodiments, the beta blocker does not haveintrinsic sympathomimetic activity (ISA). Intrinsic sympathomimeticactivity is used to refer to beta blockers that can show both agonismand antagonism at a given beta receptor, depending on the concentrationof the agent (beta blocker) and the concentration of the antagonizedagent.

In some embodiments, where the beta blocker contains one chiral center,the beta blocker is the enantiomerically enriched S-enantiomer or apharmaceutically acceptable salt thereof.

In some embodiments, the beta blocker is selected from the groupconsisting ofacebutolol, atenolol, betaxolol, bisoprolol, carteolol,celeprolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol,penbutolol, pindolol, propanolol, sotalol, esmolol, carvedilol, timolol,bopindolol, medroxalol, bucindolol, levobunolol, metipranolol,celiprolol and propafenone. In some embodiments, the beta blocker isoxprenolol. Oxprenolol is a non-selective beta blocker which possessessome intrinsic sympathomimetic activity.

In some embodiments, the beta blocker also has partial 5-HT_(1A) agonismactivity. The 5-HT_(1A) receptor is a subtype of 5-HT receptor thatbinds the endogenous neurotransmitter serotonin (5-hydroxytryptamine,5-HT). Oxprenolol is a partial 5-HT1a agonist.

S-Enantiomerically Enriched Compositions of Beta Blockers

The methods described herein comprise administration of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (for example comprising anenantiomeric excess of at least about 99% of a beta blocker). Thepresent disclosure also provides such compositions which are useful forthe methods disclosed herein.

When a compound has a chiral center, the compound can exist in opticallyactive forms. Optically active compounds have the ability to rotate theplane of plane-polarized light. In describing an optically activecompound, the prefixes R and S are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes“d” and “l” or (+) and (−) are employed to designate the sign ofrotation of plane-polarized light by the compound, with (−) or l meaningthat the compound is “levorotatory” and with (+) or d meaning that thecompound is “dextrorotatory.” There is no correlation betweennomenclature for the absolute stereochemistry and for the rotation of anenantiomer. For a given chemical structure, these compounds called“stereoisomers,” are identical except that they are mirror images of oneanother. A specific stereoisomer can also be referred to as an“enantiomer,” and a mixture of such isomers is often called an“enantiomeric” or “racemic” mixture. When a compound has one chiralcenter, there are two enantiomers: the S-enantiomer and theR-enantiomer.

The compositions described herein are enantiomerically enriched forS-enantiomer. For example, in some embodiments, the compositioncomprises an enantiomeric excess of at least about 1%, 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, or 95% of S-enantiomer of the beta blocker. In some embodiments,the composition comprises an enantiomeric excess of at least about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98′%, 99%, or 99.9% of S-enantiomerof the beta blocker. In some embodiments, the composition comprises anenantiomeric excess of at least about 90%, 95%, 98%, 99%, or 100%, up tothe detectable limit of purity, of S-enantiomer of the beta blocker. Insome embodiments, the composition comprises an enantiomeric excess ofany of about 1-4%, 5-9%, 10-11%, 20-29%, 30-39%, 40-49%, 50-59%, 60-69%,70-79%, 80-89%, 90-99, or 100% of S-enantiomer of the beta blocker. Insome embodiments, the composition comprises an enantiomeric excess of atleast about 99% or 100% of S-enantiomer of the beta blocker (i.e., pureS-enantiomer of the beta blocker). In some embodiments, the compositioncomprises an enantiomeric excess of at least 99.1, 99.2, 99.3, 99.4,99.5, 99.6, 99.7, 99.8, 99.9 or 100% of S-enantiomer of the beta blocker(i.e., pure S-enantiomer of the beta blocker). Methods of makingenantiomerically enriched compositions of beta blockers are known in theart.

In some embodiments, the beta blocker is selected from the groupconsisting of acebutolol, atenolol, betaxolol, bisoprolol, carteolol,celeprolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol,penbutolol, pindolol, propanolol, sotalol, esmolol, carvedilol, timolol,bopindolol, medroxalol, bucindolol, levobunolol, metipranolol,celiprolol and propafenone or a pharmaceutically acceptable saltthereof.

In some embodiments, the beta blocker is oxprenolol or apharmaceutically acceptable salt thereof. Oxprenolol is1-[2-(allyloxy)phenoxy]-3-(isopropylamino)propan-2-ol. The structure ofoxprenolol is shown below.

Oxprenolol is a compound with one chiral center. As a racemic mixture,there is a mixture of (R)-(+)-oxprenolol and (S)-(−)-oxprenolol.Analytical methods, such as HPLC, can be used for separation andquantification of (R)-(+)-oxprenolol and (S)-(−)-oxprenolol in mixtures.The structures of (R)-(+)-oxprenolol and (S)-(−)-oxprenolol are shownbelow.

The compositions described herein are enantiomerically enriched forS-oxprenolol. For example, in some embodiments, the compositioncomprises an enantiomeric excess of at least about 1%, 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70/%, 75%, 80%, 85%,90% or 95% of S-oxprenolol. In some embodiments, the compositioncomprises an enantiomeric excess of at least about 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99%, or 99.9% of S-oxprenolol. In someembodiments, the composition comprises an enantiomeric excess of atleast about 90%, 95%, 98%, 99%, or 100%, up to the detectable limit ofpurity, of S-oxprenolol. In some embodiments, the composition comprisesan enantiomeric excess of any of about 1-4%, 5-9%, 10-11%, 20-29%,30-39%, 40-49%, 50-59%, 60-69%, 70-79%, 80-89%, 90-99%, or 100% ofS-oxprenolol. In some embodiments, the composition comprises anenantiomeric excess of at least about 99% or 100% of S-oxprenolol (i.e.,pure S-oxprenolol). In some embodiments, the composition comprises anenantiomeric excess of at least 99.1, 99.2, 99.3, 99.4, 99.5, 99.6,99.7, 99.8, 99.9 or 100% of S-oxprenolol (i.e., pure S-oxprenolol).Methods of making enantiomerically enriched compositions of oxprenololare known in the art.

Two main routes are established for obtaining enantiomerically enrichedcompounds: (1) asymmetric syntheses and (2) racemic resolutions. (R. A.Sheldon: The Industrial Synthesis of Optically Active Compounds, inMiklös Simonyi (editor). Problems and Wonders if Chiral Molecules.Akadémiai Kiadó, Budapest, 1990, S. 349-386). The syntheses givemedium-high yields and excellent enantiomeric excess, but theresolutions are limited by 50% yield. Both technologies involvetechniques such as dynamic kinetic resolution (DKR) and membrane-basedextraction (Augustian J et al., Process Biochemistry Volume 45, Issue10, October 2010, Pages 1587-1604). One method describes enantiomerenrichment of oxprenolol up to 68% enantiomeric excess was achieved byusing a cellulose tris(3,5-dimethylphenylcarbamate) (CTPC)-coatedrayon-belt. (Yashima E, et al., Tetrahedron: Asymmetry Volume 6, Issue8, August 1995, Pages 1889-1890).

The compositions described herein in some embodiments are present inpharmaceutical compositions. The pharmaceutical compositions may furthercomprise one or more pharmaceutically acceptable carrier (orexcipients). A pharmaceutically-acceptable excipient is a substance thatis non-toxic and otherwise biologically suitable for administration to asubject. Such excipients facilitate administration of the compoundsdescribed herein and are compatible with the active ingredient. Examplesof pharmaceutically-acceptable excipients include stabilizers,lubricants, surfactants, diluents, anti-oxidants, binders, coloringagents, bulking agents, emulsifiers, or taste-modifying agents. In someembodiments, the pharmaceutical composition is sterile.

Also provided here are unit dosage forms comprising a pharmaceuticalcompositions described herein. These unit dosage forms can be stored ina suitable packaging in single or multiple unit dosages and may also befurther sterilized and sealed. Unit dosage forms can be provided, forexample, in the form of tablets, capsules, vials, and any other formsdescribed herein.

In some embodiments, there is provided a composition (such as apharmaceutical composition, for example a unit dosage) comprisingoxprenolol or a pharmaceutically acceptable salt thereof, wherein thecomposition is enantiomerically enriched for S-oxprenolol (for examplecomprising an enantiomeric excess of at least about 99% ofS-oxprenolol), wherein the amount of S-oxprenolol in the composition(such as pharmaceutical composition) is included in any of the followingranges: about 5 to about 10 mg, about 10 to about 20 mg, about 20 toabout 30 mg, about 30 to about 40 mg, about 40 to about 50 mg, about 50to about 60 mg, about 60 to about 70 mg, about 70 to about 80 mg, about80 to about 90 mg, about 90 to about 100 mg, about 100 to about 110 mg,about 110 to about 120 mg, about 120 to about 130 mg, about 130 to about140 mg, about 140 to about 150 mg, about 150 to about 160 mg. In someembodiments, the amount of S-oxprenolol in the composition is about 20to about 160 mg, including for example about 50 to about 150 mg, 80 toabout 150 mg, about 90 to about 140 mg, about 100 to about 120 mg. Insome embodiments, the composition is suitable for oral administration.

In some embodiments, the composition is provided in a slow release form.For example, oxprenolol can be administered in slow release form. (Eur JDrug Metab Pharmacokinet. 1998 April-June; 23(2): 178-84; Bennett P N,Bennett J, Bradbrook I, Francis J, John V A, Rogers H, Turner P,Warrington S J, Br J Clin Pharmacol. 1985; 19 Suppl 2:171S-175S; andWoods K L, Jack D B, Kendall M J, Halsey A, O'Donnell M L, Warrington SJ, John V A. Br J Clin Pharmacol. 1985; 19 Suppl 2:177S-184S.)

Also provided are articles of manufacture comprising the compositions,formulations, and unit dosages described herein in suitable packagingfor use in the methods of treatment, methods of administration, anddosage regimens described herein. Suitable packaging for compositionsdescribed herein are known in the art, and include, for example, vial(such as sealed vials), vessels (such as sealed vessels), ampules,bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags),and the like. These articles of manufacture may further be sterilizedand/or sealed.

Dosages and Administration Route

The dosage of the compositions described herein administered to anindividual (such as a human) may vary with the particular composition,the method of administration, and the particular stage of amyotrophiclateral sclerosis. The amount should be sufficient to produce adesirable response, such as a therapeutic or prophylactic responseagainst amyotrophic lateral sclerosis. In some embodiments, the amountof the composition is a therapeutically effective amount. In someembodiments, that amount of the composition is a prophylacticallyeffective amount. In some embodiments, the amount of total oxprenolol inthe composition is below the level that induces a toxicological effect(i.e., an effect above a clinically acceptable level of toxicity) or isat a level where a potential side effect can be controlled or toleratedwhen the composition is administered to the individual.

In some embodiments, the amount of an S-enantiomerically enrichedcomposition of a beta blocker or a pharmaceutically acceptable saltthereof (e.g., S-oxprenolol) in the composition is included in any ofthe following ranges: about 0.5 to about 5 mg, about 5 to about 10 mg,about 10 to about 15 mg, about 15 to about 20 mg, about 20 to about 25mg, about 20 to about 50 mg, about 25 to about 50 mg, about 50 to about75 mg, about 50 to about 100 mg, about 75 to about 100 mg, about 100 toabout 125 mg, about 125 to about 150 mg, about 150 to about 175 mg,about 175 to about 200 mg. In some embodiments, the amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (e.g., S-oxprenolol) in thecomposition is included in any of the following ranges: about 5 to about10 mg, about 10 to about 20 mg, about 20 to about 30 mg, about 30 toabout 40 mg, about 40 to about 50 mg, about 50 to about 60 mg, about 60to about 70 mg, about 70 to about 80 mg, about 80 to about 90 mg, about90 to about 100 mg, about 100 to about 110 mg, about 110 to about 120mg, about 120 to about 130 mg, about 130 to about 140 mg, about 140 toabout 150 mg, about 150 to about 160 mg. In some embodiments, the amountof an S-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (e.g., S-oxprenolol) in thecomposition is about 20 to about 160 mg, including for example about 50to about 150 mg, 80 to about 150 mg, about 90 to about 140 mg, about 100to about 120 mg.

In some embodiments, the amount of an S-enantiomerically enrichedcomposition of a beta blocker or a pharmaceutically acceptable saltthereof (e.g., S-oxprenolol) in the composition includes at least aboutany of 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, 10mg/kg, 15 mg/kg, or 20 mg/kg. In some embodiments, the amount of anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (e.g., S-oxprenolol) in thecomposition includes less than about any of 35 mg/kg, 30 mg/kg, 25mg/kg, 20 mg/kg, 15 mg/kg, 10 mg/kg, 5 mg/kg, 2.5 mg/kg, 2 mg/kg, 1mg/kg, 0.5 mg/kg, or 0.1 mg/kg.

Exemplary dosing frequencies include, but are not limited to, weeklywithout break; weekly, three out of four weeks; once every three weeks;once every two weeks; weekly, two out of three weeks. In someembodiments, the composition is administered about once every 2 weeks,once every 3 weeks, once every 4 weeks, once every 6 weeks, or onceevery 8 weeks. In some embodiments, the composition is administered atleast about any of 1×, 2×, 3×, 4×, 5×, 6×, or 7× (i.e., daily) a week.In some embodiments, the intervals between each administration are lessthan about any of 6 months, 3 months, 1 month, 20 days, 15, days, 12days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2days, or 1 day. In some embodiments, the intervals between eachadministration are more than about any of 1 month, 2 months, 3 months, 4months, 5 months, 6 months, 8 months, or 12 months. In some embodiments,there is no break in the dosing schedule. In some embodiments, theinterval between each administration is no more than about a week. Insome embodiments, the composition is administered daily. In someembodiments, the composition is administered twice daily. In someembodiments, the composition is administered at least once (such as atleast any of 2×, 3×, or 4×) daily.

The administration of the composition can be extended over an extendedperiod of time, such as from about a month up to about seven years orlife-long. In some embodiments, the composition is administered over aperiod of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18,24, 30, 36, 48, 60, 72, or 84 months or life-long. In some embodiments,the composition is administered over a period of at least one month,wherein the interval between each administration is no more than about aweek.

The compositions described herein can be administered to an individual(such as human) via various mutes, including, for example, intravenous,intra-arterial, intraperitoneal, intraportal, intrapulmonary, oral,inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous,intraocular, intrathecal, transmucosal, and transdermal. In someembodiments, sustained continuous release formulation of the compositionmay be used.

Once improvement of the patient's disease has occurred, the dose may beadjusted for preventative or maintenance treatment. For example, thedosage or the frequency of administration, or both, may be reduced as afunction of the symptoms, to a level at which the desired therapeutic orprophylactic effect is maintained. Of course, if symptoms have beenalleviated to an appropriate level, treatment may cease. Patients may,however, require intermittent treatment on a long-term basis upon anyrecurrence of symptoms. Patients may also require chronic treatment on along-term basis.

Pharmaceutical Formulations and Administration

The pharmaceutical compositions described herein may be formulated assolutions, emulsions, suspensions, dispersions, or inclusion complexessuch as cyclodextrins in suitable pharmaceutical solvents or carriers,or as pills, tablets, lozenges, suppositories, sachets, dragees,granules, powders, powders for reconstitution, or capsules along withsolid carriers according to conventional methods known in the art forpreparation of various dosage forms. Pharmaceutical compositions of theembodiments may be administered by a suitable route of delivery, such asoral, parenteral, rectal, nasal, topical, or ocular routes, or byinhalation. Preferably, the compositions are formulated for intravenousor oral administration.

For oral administration, the compositions may be provided in a solidform, such as a tablet or capsule, or as a solution, emulsion, orsuspension. Oral tablets may include the active ingredient(s) mixed withcompatible pharmaceutically acceptable excipients such as diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservative agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquidoral excipients include ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are exemplary disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid, or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating. The oral formulationsmay be presented as discrete units such as capsules, cachets or tablets,each containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient(s) may be mixed witha solid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil such aspeanut oil or olive oil, liquid paraffin, a mixture of mono anddi-glycerides of short chain fatty acids, polyethylene glycol 400, orpropylene glycol.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder (eg povidone, gelatin, hydroxypropylmethyl cellulose), lubricant,inert diluent, preservative, disintegrant (eg sodium starch glycolate,cross-linked povidone, cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Moulded tablets may be made bymoulding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein using, for example,hydroxypropylmethylcellulose in varying proportions to provide desiredrelease profile.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions, or syrups, or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water,preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

For parenteral use, including intravenous, intramuscular,intraperitoneal, intranasal, or subcutaneous routes, the compositionsmay be provided in sterile aqueous solutions or suspensions, buffered toan appropriate pH and isotonicity or in parenterally acceptable oil.Suitable aqueous vehicles include Ringer's solution and isotonic sodiumchloride. Such forms may be presented in unit-dose form such as ampoulesor disposable injection devices, in multi-dose forms such as vials fromwhich the appropriate dose may be withdrawn, or in a solid form orpre-concentrate that can be used to prepare an injectable formulation.Formulations suitable for parenteral including intravenousadministration include aqueous and non-aqueous sterile injectionsolutions which may contain anti-oxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Theformulations may be presented in unit-dose or multi-dose containers, forexample sealed ampoules and vials, and may be stored in a freeze-dried(lyophilised) condition requiring only the addition of the sterileliquid carrier, for example water for injections, immediately prior touse. Extemporaneous injection solutions and suspensions may be preparedfrom sterile powders, granules and tablets of the kind previouslydescribed.

Preferred unit dosage formulations are those containing a daily dose orunit, daily sub-dose or an appropriate fraction thereof, of an activeingredient.

Drug Combinations

The methods of the embodiments comprise administering an effectiveamount of at least one compound of the embodiments; optionally thecompound may be administered in combination with one or more additionaltherapeutic agents, particularly therapeutic agents known to be usefulfor treating a amyotrophic lateral sclerosis afflicting the subject.

The additional active ingredients may be administered in a separatepharmaceutical composition from a compound of the embodiments or may beincluded with a compound of the embodiments in a single pharmaceuticalcomposition. The additional active ingredients may be administeredsimultaneously with, prior to, or after administration of a compound ofthe embodiments.

In certain embodiments, the additional therapeutic agent is selectedfrom the group consisting of CK-2017357, olesoxime (TRO 19622),arimoclomol, riluzole, tretionin and pioglitazone HCl, AVP-923,memantine, talampanel, tauroursodeoxycholic acid (TUDCA), thalidomide,olanzapine, KNS-760704, lithium carbonate, NPOOI, ONO-2506PO, tamoxifen,creatine monohydrate, coenzyme Q10, YAM80, sodium phenylbutyrate,pyrimethamine, R(+)pramipexole dihydrochloride monohydrate, vitamin E,minocycline, topiramate, gabapentin, AEOL-10150, stem cell injections.SB-509, autologous hone marrow-derived stem cells, cefiriaxone, E0302(mecobalamin), MCI-186, glatiramer acetate, insulin-like growth factor-1(IGF-1), ISIS 333611, sNN0029, GSK1223249, brain-derived neurotrophicfactor (BDNF), and anti-CD40L antibody.

Kits

The present application also provides kits, medicines, compositions, andunit dosage forms for use in any of the methods described herein.

Kits provided herein include one or more containers comprising any oneof the compositions described herein and/or other agent(s), and in someembodiments, further comprise instructions for use in accordance withany of the methods described herein. The kit may further comprise adescription of selection of individual suitable for treatment.Instructions supplied in the kits of the invention are typically writteninstructions on a label or package insert (e.g., a paper sheet includedin the kit), but machine-readable instructions (e.g., instructionscarried on a magnetic or optical storage disk) are also acceptable.

For example, in some embodiments, the kit comprises a) anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (e.g., S-oxprenolol) and apharmaceutically acceptable carrier and b) instructions foradministering the composition for treatment of amyotrophic lateralsclerosis.

The kits of the invention are in suitable packaging. Suitable packaginginclude, but is not limited to, vials, bottles, jars, flexible packaging(e.g., sealed Mylar or plastic bags), and the like. Kits may optionallyprovide additional components such as buffers and interpretativeinformation. The present application thus also provides articles ofmanufacture, which include vials (such as sealed vials), bottles, jars,flexible packaging, and the like.

The instructions relating to the use of the compositions generallyinclude information as to dosage, dosing schedule, and route ofadministration for the intended treatment. The containers may be unitdoses, bulk packages (e.g., multi-dose packages) or sub-unit doses. Forexample, kits may be provided that contain sufficient dosages ofS-oxprenolol as disclosed herein to provide effective treatment of anindividual for an extended period, such as any of a week, 8 days, 9days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9months, or more. Kits may also include multiple unit doses of thepharmaceutical compositions and instructions for use and packaged inquantities sufficient for storage and use in pharmacies, for example,hospital pharmacies and compounding pharmacies.

Also provided are medicines, compositions, and unit dosage forms usefulfor the methods described herein. For example, the present disclosureprovides, in some embodiments, an S-enantiomerically enrichedcomposition of a beta blocker or a pharmaceutically acceptable saltthereof (e.g., S-oxprenolol) for treating amyotrophic lateral sclerosisin an individual having amyotrophic lateral sclerosis. The presentdisclosure provides, in some embodiments, an S-enantiomerically enrichedcomposition of a beta blocker or a pharmaceutically acceptable saltthereof (e.g., S-oxprenolol) for prolonging survival of an individualhaving amyotrophic lateral sclerosis. The present disclosure provides,in some embodiments, an S-enantiomerically enriched composition of abeta blocker or a pharmaceutically acceptable salt thereof (e.g.,S-oxprenolol) for delaying the development of amyotrophic lateralsclerosis in an individual having amyotrophic lateral sclerosis. Thepresent disclosure provides, in some embodiments, an S-enantiomericallyenriched composition of a beta blocker or a pharmaceutically acceptablesalt thereof (e.g., S-oxprenolol) for preventing lean mass loss of anindividual having amyotrophic lateral sclerosis. The present disclosureprovides, in some embodiments, an S-enantiomerically enrichedcomposition of a beta blocker or a pharmaceutically acceptable saltthereof (e.g., S-oxprenolol) for preventing muscle wasting of anindividual having amyotrophic lateral sclerosis. The present disclosureprovides, in some embodiments, an S-enantiomerically enrichedcomposition of a beta blocker or a pharmaceutically acceptable saltthereof (e.g., S-oxprenolol) for improving quality of life in anindividual having amyotrophic lateral sclerosis.

For example, the present disclosure provides, in some embodiments, anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (e.g., S-oxprenolol) for themanufacture of a medicament for treating amyotrophic lateral sclerosisin an individual having amyotrophic lateral sclerosis. The presentdisclosure provides, in some embodiments, an S-enantiomerically enrichedcomposition of a beta blocker or a pharmaceutically acceptable saltthereof (e.g., S-oxprenolol) for the manufacture of a medicament forprolonging survival of an individual having amyotrophic lateralsclerosis. The present disclosure provides, in some embodiments, anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (e.g., S-oxprenolol) for themanufacture of a medicament for delaying the development of amyotrophiclateral sclerosis in an individual having amyotrophic lateral sclerosis.The present disclosure provides, in some embodiments, anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (e.g., S-oxprenolol) for themanufacture of a medicament for preventing lean mass loss of anindividual having amyotrophic lateral sclerosis. The present disclosureprovides, in some embodiments, an S-enantiomerically enrichedcomposition of a beta blocker or a pharmaceutically acceptable saltthereof (e.g., S-oxprenolol) for the manufacture of a medicament forpreventing muscle wasting of an individual having amyotrophic lateralsclerosis. The present disclosure provides, in some embodiments, anS-enantiomerically enriched composition of a beta blocker or apharmaceutically acceptable salt thereof (e.g., S-oxprenolol) for themanufacture of a medicament for improving quality of life in anindividual having amyotrophic lateral sclerosis.

Those skilled in the art will recognize that several embodiments arepossible within the scope and spirit of this invention. The inventionwill now be described in greater detail by reference to the followingnon-limiting examples. The following examples further illustrate theinvention but, of course, should not be construed as in any way limitingits scope.

Examples Example 1 Synthesis of S-Oxprenolol

The synthesis of S-oxprenolol is shown in Scheme 1.

Preparation of 2-(allyloxy)phenol

To a solution of catechol (1) (40.0 g, 0.364 mol) in acetone (160 mL)was added potassium carbonate (50.0 g, 0.363 mol) portion-wise at roomtemperature, over a period of 30 minutes. After the addition wascomplete the mixture was stirred at room temperature for 1 hour. Allylbromide (31.0 mL, 0.358 mol) was then added over a period of 30 minutes,and the reaction heated to 60-70° C., for 6 hours. The reaction wasallowed to cool, then water and ethyl acetate were added and the mixturewas separated. The organic layer was dried (MgSO₄) and the solventevaporated to give 2-(allyloxy)phenol (2) (46.2 g) as a 7:3 mixture ofmono and bis alkylated material.

¹H NMR (300 MHz, CDCl₃) δ 6.93-6.77 (m, 4H), 6.05 (m, 1H), 5.41 (dd,1H), 5.30 (m, 1H), 4.61 (d, 2H). LCMS: Rt 0.70 min, [M+H]⁺ 148.9, 70%.

Preparation of S-oxprenolol

CsF (22.8 g, 0.150 mol) was added to a solution of 2-(allyloxy)phenol(7.50 g, 0.050 mol) in DMF (100 mL) and stirred for 1 hour at roomtemperature. (S)-Glycidyl nosylate (13.0 g, 0.050 mol) was added and thereaction stirred for 72 hours at room temperature, then added dropwiseto ^(i)PrNH₂ (97 mL, 1.26 mol) and stirred overnight. The reactionmixture was diluted with EtOAc (150 mL) and water (200 mL) and thesolids removed by filtration. The phases were separated and the organiclayer washed with water (100 mL), then brine (100 mL), dried over MgSO₄and concentrated. Purification by column chromatography (5-10% MeOH/DCMthen 5% (17% NH₃/MeOH) in DCM) gave (S)-oxprenolol (4.67 g, 20%) as abrown solid.

¹H NMR (300 MHz, CDCl₃) δ 6.92-6.89 (m, 2H), 6.82-6.79 (m, 2H), 5.99 (m,1H), 5.37 (d, 1H), 5.21 (d, 1H), 4.87 (br s, 1H), 4.51 (d, 2H), 3.85 (d,2H), 3.80 (m, 1H), 2.69-2.61 (m, 2H), 2.47 (m, 1H), 1.48 (br s, 1H),0.93 (d, 6H).

LCMS: Rt 1.78 min, [M+H]⁺ 266.1, 100%.

Example 2 Synthesis of R-Oxprenolol

The synthesis of S-oxprenolol is shown in Scheme 2.

Preparation of R-oxprenolol

CsF (2.95 g, 19.4 mmol) and K₂CO₃ (17.3 & 125 mmol) were added to asolution of 2-(allyloxy)phenol (14.4 g, 96.2 mmol) in DMF (250 mL) andstirred for 30 minutes at room temperature. (R)-Glycidyl nosylate (25.0g, 96.4 mmol) was added and the reaction stirred for 48 hours at roomtemperature. ^(i)PrNH₂ (190 mL, 2.21 mol) was added in one portion andthe reaction stirred for 72 hours. The reaction mixture was diluted withwater (1.0 L) and extracted with EtOAc (3×300 mL). The combined organicswere washed with HCl (2.0 M, 3×300 mL). The aqueous layer was pHadjusted to pH 12 with NaOH (2.0 M) and extracted into EtOAc (2×500 mL).This was washed with 1:1 water/brine (3×500 mL), then with brine (500mL), dried over Na₂SO₄ and concentrated. The crude solid was trituratedfrom heptanes, filtered and dried under vacuum at 40° C. overnight togive (R)-oxprenolol (24.5 g, 69%) as a brown solid.

¹H NMR (300 MHz, CDCl₃) δ 6.92-6.89 (m, 2H), 6.82-6.79 (m, 2H), 5.99 (m,1H), 5.37 (d, 1H), 5.21 (d, 1H), 4.87 (br s, 1H), 4.51 (d, 2H), 3.85 (d,2H), 3.80 (m, 1H), 2.69-2.61 (m, 2H), 2.47 (m, 1H), 1.48 (br s, 1H),0.93 (d, 6H).

LCMS: Rt 1.79 min, [M+H]⁺ 266.1, 99%.

Example 3 Study Protocol with B6SJL-Tg(SOD1*G93A)1Gur/J ALS Mouse Model

Transgenic mice over-expressing a high copy number (25 copies) ofmutated human SOD1 gene with a G93A point mutation. i.e., B6SJL-TgN[SOD1-G93A]1Gur (G1H-G93A transgenic mice, JR2726; Hemizygote) (Gurney ME, et al., Science, 264, 1772-1775, 1994) (“G93A SOD1 B6SJL hybrid(G93A) model”), were used. As shown in a diagram in FIG. 1, thetransgenic mice display muscle weakness and atrophy by 90 to 100 days ofage, and typically die near 130 days of age.

An intervention study was performed with S-oxprenolol (10 mg/kg/day) inthe G93A SOD1 B6SJL hybrid (G93A) model after onset of ALS. Onset ofdisease was defined as peak body weight as well as the beam walk andsplay neurological scores as suggested by Ludolph et al. 2007. (LudolphA C, Bendotti C, Blaugrund E, Hengerer B, Loffler J P, Martin J,Meininger V, Meyer T. Moussaoui S, Robberecht W, Scott S, Silani V, VanDen Berg L H (ENMC Group For The Establishment Of Guidelines For TheConduct Of Preclinical And Proof Of Concept Studies In ALS/MND Models).2007. Guidelines for the preclinical in viva evaluation ofpharmacological active drugs for ALS/MND: Report on the 142nd ENMCinternational workshop. Amyotrophic Lateral Sclerosis 8: 217-223.) Therewere 15 mice in the placebo group. There were 16 mice in theS-oxprenolol group.

The primary endpoint was survival, humanely defined as the ability ofthe animal to right itself in 30 seconds after being laid on its side.Secondary endpoints were body weight, body composition, spontaneousactivity and food intake. Body weight of the animals was assessed weeklyuntil onset of disease. Additionally, body composition (fat mass andlean body mass) was assessed using NMR scans (EchoMRI-100. Echo MedicalSystems, Houston, USA) every 4 days. After onset of disease, body weightand body composition were assessed every two days until the end of thestudy. All personal handling the animals was strictly blinded to therandomized treatment allocation.

Example 4 Effect of S-Oxprenolol on Survival

To study the effect of S-oxprenolol on survival, survival was monitoredover time. FIG. 2 shows the percent survival of mice that wereadministered with S-oxprenolol at dosages of 10 mg/kg/day. As shown inFIG. 2, mice receiving S-oxprenolol had longer survival than those inthe placebo group. Treatment of G93A mice with 10 mg/kg/day ofS-oxprenolol after onset of ALS significantly improved survival by about33% compared to placebo treated mice (56 vs 42 days after onset,respectively. HR: 0.39, 95% CI: 0.171-0.88, p=0.0241, FIG. 2). Mediansurvival was improved from 28 days (placebo) to 37 days (S-oxprenolol,ratio: 1.32, 95% CI: 0.83-1.81).

FIG. 3 shows the percent survival of mice that were administeredS-oxprenolol at a dosage of 10 mg/kg/day. One control group receivedS-pindolol at its preferred dosage of 3 mg/kg/day. As shown in FIG. 3.S-oxprenolol was significantly superior to either placebo or S-pindololat its preferred dose. The median survival after onset of ALS symptomswas 28 days for the placebo group; 31 days for the S-pindolol group; and37 days for the S-oxprenolol group.

FIG. 4 shows the percent survival of mice that were administeredS-oxprenolol at a dosage of 10 mg/kg/day, R-oxprenolol at a dosage of 10mg/kg/day, oxprenolol at a dosage of 20 mg/kg/day, riluzole at a dosageof 30 mg/kg/day, or propanolol at a dosage of 10 mg/kg/day. There wasalso a placebo group. As shown in FIG. 4, S-oxprenolol was significantlysuperior to either placebo or the other compounds.

Example 5 Effect of S-Oxprenolol on Body Weight

To study the effect of S-oxprenolol on body weight, body weight wasmonitored over time.

FIG. 5 shows the change of body weight (in grams per day alive afteronset of ALS symptoms) per survival day after ALS onset in miceadministered S-oxprenolol at a dosage of 10 mg/kg/day or S-pindolol atpreferred dosage of 3 mg/kg/day. As shown in FIG. 5, mice receivingS-oxprenolol had body weight loss that was close to those administeredS-pindolol. Mice receiving S-oxprenolol had less body weight loss thanthose in the placebo group.

Example 6 Effects of S-Oxprenolol on Preserving Lean Body Mass

To study the effect of the test compounds on lean body mass, lean masswas determined at the end of the study.

In this experiment, all mice were killed using the 30 seconds endpointand hence all mice were equally diseased at the end of the study. FIG. 6shows the change in lean body mass (in grams) of mice that wereadministered S-oxprenolol at a dosage of 10 mg/kg/day. As shown in FIG.6, rats receiving S-oxprenolol had less change in lean body mass thanthose receiving a placebo. Wasting of lean mass was reduced by about 40%by active treatment compared to placebo (p=0.18, FIG. 6). This effectshows that S-oxprenolol is effective in preserving lean body mass.

FIG. 7 shows the change in lean body mass (in grams per day alive afteronset of ALS symptoms) per survival day after ALS onset of mice thatwere administered S-oxprenolol at a dosage of 10 mg/kg/day or S-pindololat preferred dosage of 3 mg/kg/day. As shown in FIG. 6, rats receivingS-oxprenolol had less change in lean body mass than those receivingS-pindolol.

Example 7 Effects of S-Oxprenolol on Skeletal Muscle Atrophy

To study the effect of the test compounds on skeletal muscle atrophy,the skeletal muscle mass were determined at the end of the study.

FIGS. 8-11 show the mass of various types of skeletal muscle (in grams)of mice populations that were administered S-oxprenolol at a dosage of10 mg/kg/day or a placebo. FIG. 8 shows results for gastroenemius muscleweight plotted with days after onset for the placebo group. A trend fora correlation of days after onset (=survival) and gastrocnemius weightwas seen in placebo-treated mice. (R:−0.56, p=0.18) FIG. 9 shows resultsfor gastrocnemius muscle weight plotted with days after onset for theS-oxprenolol group. FIG. 9 shows that with administration ofS-oxprenolol, the gastrocnemius weight in the G93A ALS model is steady.There is no correlation of days after onset (=survival) forgastrocnemius weight. (R:−0.03, p=0.94)

FIG. 10 shows results for tibialis anterior muscle weight plotted withdays after onset for the placebo group. A trend for a correlation ofdays after onset (=survival) and tibialis anterior muscle weight wasseen in placebo-treated mice. (R:−0.67, p=0.097) FIG. 11 shows resultsfor tibialis anterior muscle weight plotted with days after onset forthe S-oxprenolol group. FIG. 11 shows that with administration ofS-oxprenolol, the tibialis anterior muscle weight in the G93A ALS modelis steady. There is no correlation of days after onset (=survival) fortibialis anterior muscle. (R:0.15, p=0.72)

The loss of mass of the mixed-fiber type muscle gastrocnemius showed atrend for a correlation of survival (=days after onset of disease. FIG.8), while mice treated with S-oxprenolol (FIG. 9) showed no correlation,indicating a muscle protective role of S-oxprenolol. The loss of mass ofthe mixed-fiber type muscle tibialis showed a strong trend for acorrelation of survival (=days after onset of disease, FIG. 10), whilemice treated with S-oxprenolol showed no correlation (FIG. 11), againindicating a muscle protective role of S-oxprenolol.

Example 8 Effects of S-Oxprenolol on Preserving Fat Mass

To study the effect of the test compounds on fat mass, the fat mass weredetermined at the end of the study.

FIG. 12 shows the change in fat mass (in grams) of mice administeredS-oxprenolol. As shown in FIG. 12, rats receiving S-oxprenolol had noreduction in fat mass than those in the placebo group. S-oxprenolol hadno effect on the loss of fat mass (p>0.5. FIG. 12).

FIG. 13 shows the change in fat mass (in grams per day alive after onsetof ALS symptoms) per survival day after ALS onset of mice that wereadministered S-oxprenolol at a dosage of 10 mg/kg/day or S-pindolol atpreferred dosage of 3 mg/kg/day. As shown in FIG. 13, rats receivingS-oxprenolol had less change in fat mass than those receivingS-pindolol.

The difference between FIGS. 12 and 13 is explained by the survival. Theoverall loss of fat mass is equal on the day the animals are euthanized.But mice treated with S-oxprenolol lived longer and therefore the lossof fat mass per day alive after onset of ALS symptoms is lower (=overallfat loss divided by number of days alive alter ALS onset).

Example 9 Effects of S-Oxprenolol on Improving Outcome of ALS Comparedto R-Oxprenolol and Rilutek

To study the effect of S-oxprenolol on survival compared to R-oxprenololand rilutek, survival was monitored over time. Rilutek (Riluzole,structure shown below) is used for treating ALS.

FIG. 14 shows the percent survival of mice that were administered withS-oxprenolol at dosages of 10 mg/kg/day or 20 mg/kg/day. Other groups ofmice were administered rilutek at a dosage of 30 mg/kg/day; propanololat a dosage of 10 mg/kg/day; oxprenolol (racemic) at a dosage of 20mg/kg/day; R-oxprenolol at a dosage of 10 mg/kg/day or 20 mg/kg/day; ora placebo. The number of mice in each population is indicated as “n” inFIG. 14. As shown in FIG. 14, mice receiving S-oxprenolol at a dosage of20 mg/kg/day had longer survival than other groups.

The statistical data for FIG. 14 is shown below. “HR” refers to hazardratio. “95% CI” is confidence interval. “p” refers to p value.

TABLE 1 Statistical data for FIG. 14 (for all mice) Comparison (dosagein mg/kg/day) HR 95% CI p value Rilutek (30) vs. placebo 0.89 0.55-1.460.65 Propanolol (10) vs. placebo 0.73 0.45-1.18 0.20 Oxprenolol (20) vs.placebo 0.66 0.40-1.07 0.09 R-Oxprenolol (10) vs. placebo 0.57 0.35-0.930.0227 R-Oxprenolol (20) vs. placebo 0.54 0.34-0.88 0.013 S-Oxprenolol(10) vs. placebo 0.71 0.46-1.10 0.13 S-Oxprenolol (20) vs. placebo 0.450.27-0.73 0.0014 Rilutek (30) vs. S-Oxprenolol (20) 2.07 1.17-3.670.0129 Propanolol (10) vs. S-Oxprenolol (10) 1.06 0.65-1.74 0.82Propanolol (10) vs. S-Oxprenolol (20) 1.77 0.99-3.15 0.0532 R-Oxprenolol(20) vs. S-Oxprenolol 1.32 0.77-2.28 0.31 (20) S-Oxprenolol (20) vs.placebo 0.45 0.27-0.73 0.0014

FIG. 15 shows the percent survival of male mice that were administeredwith S-oxprenolol at dosages of 10 mg/kg/day or 20 mg/kg/day. Othergroups of male mice were administered rilutek at a dosage of 30mg/kg/day; propanolol at a dosage of 10 mg/kg/day; oxprenolol (racemic)at a dosage of 20 mg/kg/day; R-oxprenolol at a dosage of 10 mg/kg/day or20 mg/kg/day; or a placebo. The number of male mice in each populationis indicated as “n” in FIG. 15. As shown in FIG. 15, male mice receivingS-oxprenolol at a dosage of 20 mg/kg/day had longer survival than othergroups.

The statistical data for FIG. 15 is shown below. “HR” refers to hazardratio. “95% CI” is confidence interval. “p” refers to p value.

TABLE 2 Statistical data for FIG. 15 (for male mice) Comparison (dosagein mg/kg/day) HR 95% CI p value Rilutek (30) vs. placebo 0.63 0.30-1.290.21 Propanolol (10) vs. placebo 0.59 0.29-1.21 0.15 Oxprenolol (20) vs.placebo 0.38 0.18-0.80 0.0114 R-Oxprenolol (10) vs. placebo 0.490.23-0.99 0.0492 R-Oxprenolol (20) vs. placebo 0.41 0.19-0.86 0.0176S-Oxprenolol (10) vs. placebo 0.46 0.23-0.92 0.0289 S-Oxprenolol (20)vs. placebo 0.39 0.19-0.83 0.0139 Rilutek (30) vs. S-Oxprenolol (20)1.96 0.85-4.51 0.11 Propanolol (10) vs. S-Oxprenolol (10) 1.64 0.75-3.480.22 Propanolol (10) vs. S-Oxprenolol (20) 1.98 0.88-4.49 0.099R-Oxprenolol (20) vs. S-Oxprenolol 1.24 0.57-2.69 0.58 (20) S-Oxprenolol(20) vs. placebo 0.39 0.19-0.83 0.0139

FIG. 16 shows the percent survival of female mice that were administeredwith S-oxprenolol at dosages of 10 mg/kg/day or 20 mg/kg/day. Othergroups of female mice were administered rilutek at a dosage of 30mg/kg/day; propanolol at a dosage of 10 mg/kg/day; oxprenolol (racemic)at a dosage of 20 mg/kg/day; R-oxprenolol at a dosage of 10 mg/kg/day or20 mg/kg/day; or a placebo. The number of female mice in each populationis indicated as “n” in FIG. 16. As shown in FIG. 16, female micereceiving S-oxprenolol at a dosage of 20 mg/kg/day had longer survivalthan other groups.

The statistical data for FIG. 16 is shown below. “HR” refers to hazardratio. “95% CI” is confidence interval. “p” refers to p value.

TABLE 3 Statistical data for FIG. 16 (for female mice) Comparison(dosage in mg/kg/day) HR 95% CI p value Rilutek (30) vs. placebo 1.080.55-2.15 0.82 Propanolol (10) vs. placebo 0.71 0.36-1.39 0.32Oxprenolol (20) vs. placebo 1.03 0.52-2.02 0.94 R-Oxprenolol (10) vs.placebo 0.60 0.31-1.15 0.13 R-Oxprenolol (20) vs. placebo 0.41 0.31-1.160.13 S-Oxprenolol (10) vs. placebo 0.96 0.53-1.73 0.89 S-Oxprenolol (20)vs. placebo 0.53 0.27-1.02 0.058 Rilutek (30) vs. S-Oxprenolol (20) 2.040.92-4.51 0.077 Propanolol (10) vs. S-Oxprenolol (10) 0.75 0.38-1.460.39 Propanolol (10) vs. S-Oxprenolol (20) 1.49 0.67-3.34 0.32R-Oxprenolol (20) vs. S-Oxprenolol 1.26 0.59-2.72 0.55 (20) S-Oxprenolol(20) vs. placebo 0.53 0.27-1.02 0.058

FIGS. 17-19 show changes in disease progression of scores in testedmice. The disease progression score is based on the JAX SOP (Ludolph AC, Bendotti C, Blaugrund E, Hengerer B, Loffler J P, Martin J, MeiningerV, Meyer T, Moussaoui S, Robberecht W. Scott S. Silani V, Van Den Berg LH (ENMC Group For The Establishment Of Guidelines For The Conduct OfPrecinical And Proof Of Concept Studies In ALS/MND Models). 2007, whichis incorporated by reference).

FIG. 17 shows the percent of mice that improved from disease progressionof score 1 to score 2 that were administered with S-oxprenolol atdosages of 10 mg/kg/day or 20 mg/kg/day. Other groups of mice wereadministered rilutek at a dosage of 30 mg/kg/day; propanolol at a dosageof 10 mg/kg/day; oxprenolol (racemic) at a dosage of 20 mg/kg/day;R-oxprenolol at a dosage of 10 mg/kg/day or 20 mg/kg/day; or a placebo.

The statistical data for FIG. 17 is shown below. “HR” refers to hazardratio. “95% CI” is confidence interval. “p” refers to p value.

TABLE 4 Statistical data for FIG. 17 (Progression from score 1 to score2) Comparison (dosage in mg/kg/day) HR 95% CI p value Rilutek vs.placebo 0.82 0.48-1.40 0.47 Propanolol vs. placebo 0.64 0.39-1.06 0.086Oxprenolol vs. placebo 0.60 0.36-1.01 0.053 R-Oxprenolol (10) vs.placebo 0.47 0.28-0.79 0.0047 R-Oxprenolol (20) vs. placebo 0.540.32-0.90 0.0176 S-Oxprenolol (10) vs. placebo 0.56 0.35-0.91 0.0189S-Oxprenolol (20) vs. placebo 0.51 0.31-0.87 0.0128 Rilutek vs.S-Oxprenolol (10) 1.68 0.92-3.08 0.093 Rilutek vs. S-Oxprenolol (20)1.73 0.91-3.29 0.094 Propanolol vs. S-Oxprenolol (10) 1.27 0.73-2.210.39 Propanolol vs. S-Oxprenolol (20) 1.49 0.82-2.69 0.19 R-Oxprenolol(10) vs. S-Oxprenolol 0.73 0.42-1.27 0.27 (10) S-Oxprenolol (20) vs.S-Oxprenolol 1.17 0.65-2.09 0.60 (20)

FIG. 18 shows the percent of mice that improved from disease progressionof score 2 to score 3 that were administered with S-oxprenolol atdosages of 10 mg/kg/day or 20 mg/kg/day. Other groups of mice wereadministered rilutek at a dosage of 30 mg/kg/day; propanolol at a dosageof 10 mg/kg/day; oxprenolol (racemic) at a dosage of 20 mg/kg/day;R-oxprenolol at a dosage of 10 mg/kg/day or 20 mg/kg/day; or a placebo.

The statistical data for FIG. 18 is shown below. “HR” refers to hazardratio. “95% CI” is confidence interval. “p” refers to p value.

TABLE 5 Statistical data for FIG. 18 (Progression from score 2 to score3) Comparison (dosage in mg/kg/day) HR 95% CI p value Rilutek vs.placebo 0.68 0.37-1.24 0.21 Propanolol vs. placebo 0.99 0.58-1.69 0.97Oxprenolol vs. placebo 0.77 0.44-1.33 0.35 R-Oxprenolol (10) vs. placebo1.04 0.59-1.82 0.91 R-Oxprenolol (20) vs. placebo 0.74 0.43-1.27 0.27S-Oxprenolol (10) vs. placebo 1.07 0.64-1.79 0.79 S-Oxprenolol (20) vs.placebo 0.64 0.37-1.12 0.12 Rilutek vs. S-Oxprenolol (10) 0.69 0.38-1.280.24 Rilutek vs. S-Oxprenolol (20) 1.06 0.54-2.06 0.87 Propanolol vs.S-Oxprenolol (10) 0.84 0.48-1.46 0.54 Propanolol vs. S-Oxprenolol (20)1.46 0.81-2.64 0.21 R-Oxprenolol (10) vs. S-Oxprenolol 0.95 0.53-1.690.87 (10) S-Oxprenolol (20) vs. S-Oxprenolol 1.20 0.66-2.19 0.55 (20)

FIG. 19 shows the percent of mice that improved from disease progressionof score 1 to score 3 that were administered with S-oxprenolol atdosages of 10 mg/kg/day or 20 mg/kg/day. Other groups of mice wereadministered rilutek at a dosage of 30 mg/kg/day; propanolol at a dosageof 10 mg/kg/day; oxprenolol (racemic) at a dosage of 20 mg/kg/day;R-oxprenolol at a dosage of 10 mg/kg/day or 20 mg/kg/day; or a placebo.

The statistical data for FIG. 19 is shown below. “HR” refers to hazardratio. “95% CI” is confidence interval. “p” refers to p value.

TABLE 6 Statistical data for FIG. 19 (Progression from score 1 to score3) Comparison (dosage in mg/kg/day) HR 95% CI p value Rilutek vs.placebo 0.76 0.42-1.37 0.84 Propanolol vs. placebo 0.72 0.43-1.21 0.21Oxprenolol vs. placebo 0.60 0.35-1.01 0.055 R-Oxprenolol (10) vs.placebo 0.60 0.35-1.02 0.060 R-Oxprenolol (20) vs. placebo 0.630.37-1.07 0.086 S-Oxprenolol (10) vs. placebo 0.73 0.45-1.20 0.22S-Oxprenolol (20) vs. placebo 0.47 0.28-0.81 0.0061 Rilutek vs.S-Oxprenolol (10) 1.13 0.59-2.14 0.14 Rilutek vs. S-Oxprenolol (20) 1.960.94-4.08 0.072 Propanolol vs. S-Oxprenolol (10) 0.92 0.53-1.57 0.75Propanolol vs. S-Oxprenolol (20) 1.67 0.91-3.06 0.099 R-Oxprenolol (10)vs. S-Oxprenolol 0.78 0.45-1.36 0.17 (10) S-Oxprenolol (20) vs.S-Oxprenolol 1.48 0.79-2.75 0.22 (20)

Example 10 Effects of S-Oxprenolol Compared to R-Oxprenolol and Rilutek

To study the effect of S-oxprenolol on body weight, body weight wasmonitored over time. FIG. 20A-20C show the change of body weight in miceadministered S-oxprenolol at a dosage of 20 mg/kg/day or 10 mg/kg/day;R-oxprenolol at a dosage of 20 mg/kg/day; rilutek at a dosage of 30mg/kg/day; or placebo. FIG. 20A shows results for all mice. FIG. 20Bshows results for male mice. FIG. 20C shows results for female mice. Thenumber of all mice in the population is indicated as “n” in at thebottom of FIGS. 20A-20C.

To study the effect of the test compounds on lean body mass, lean masswas determined at the end of the study. In this experiment, all micewere killed using the 30 seconds endpoint and hence all mice wereequally diseased at the end of the study. FIGS. 20D-20F show the changein lean body mass (in grams) of mice that were administered S-oxprenololat a dosage of 20 mg/kg/day or 10 mg/kg/day; R-oxprenolol at a dosage of20 mg/kg/day; rilutek at a dosage of 30 mg/kg/day; or placebo. FIG. 20Dshows results for all mice. FIG. 20E shows results for male mice. FIG.20F shows results for female mice. The number of all mice in thepopulation is indicated as “n” in at the bottom of FIGS. 20D-20F.

To study the effect of the test compounds on fat mass, the fat mass weredetermined at the end of the study. FIGS. 20G-20I show the change in fatmass (in grams) of mice administered S-oxprenolol at a dosage of 20mg/kg/day or 10 mg/kg/day; R-oxprenolol at a dosage of 20 mg/kg/day;rilutek at a dosage of 30 mg/kg/day; or placebo. FIG. 20G shows resultsfor all mice. FIG. 20H shows results for male mice. FIG. 20I showsresults for female mice. The number of all mice in the population isindicated as “n” in at the bottom of FIGS. 20G-20I.

FIGS. 21A-21C show results for heart weight at the end of the study.FIGS. 21A-21C show the heart weight (in milligrams) of mice administeredS-oxprenolol at a dosage of 20 mg/kg/day or 10 mg/kg/day; R-oxprenololat a dosage of 20 mg/kg/day; rilutek at a dosage of 30 mg/kg/day; orplacebo. FIG. 21A shows results for all mice. FIG. 21B shows results formale mice. FIG. 21C shows results for female mice. The number of allmice in the population is indicated as “n” in at the bottom of FIGS.21A-21C.

FIGS. 21D-21F show results for gastrocnemius muscle weight at the end ofthe study. FIGS. 21D-21F show the gastrocnemius muscle weight (inmilligrams) of mice administered S-oxprenolol at a dosage of 20mg/kg/day or 10 mg/kg/day; R-oxprenolol at a dosage of 20 mg/kg/day;rilutek at a dosage of 30 mg/kg/day; or placebo. FIG. 21D shows resultsfor all mice. FIG. 21E shows results for male mice. FIG. 21F showsresults for female mice. The number of all mice in the population isindicated as “n” in at the bottom of FIGS. 20D-20F.

FIGS. 21G-21I show results for tibialis muscle weight at the end of thestudy. FIGS. 21G-21I show the tibialis muscle weight (in milligrams) ofmice administered S-oxprenolol at a dosage of 20 mg/kg/day or 10mg/kg/day; R-oxprenolol at a dosage of 20 mg/kg/day; rilutek at a dosageof 30 mg/kg/day; or placebo. FIG. 21G shows results for all mice. FIG.21H shows results for male mice. FIG. 21I shows results for female mice.The number of all mice in the population is indicated as “n” in at thebottom of FIGS. 21G-21I.

The following tables show results for mice administered withS-oxprenolol at a dosage of 20 mg/kg/day or 10 mg/kg/day; R-oxprenololat a dosage of 20 mg/kg/day or 10 mg/kg/day; rilutek at a dosage of 30mg/kg/day; propanolol at a dosage of 10 mg/kg/day; oxprenolol (racemic)at a dosage of 20 mg/kg/day; or placebo. The results for delta bodyweight, delta lean mass, delta fat mass, average delta body weight,average delta lean mass, average delta fat mass, heart mass,gastrocnemius mass, soleus mass, EDL, and BAT were obtained with testsaccording the examples herein.

TABLE 7 Data for all mice administered with S-oxprenolol, R-oxprenolol,rilutek, propanolol, oxprenolol (racemic), or placebo. 30 mg/kg/d 10mg/kg/d 20 mg/kg/d placebo rilutek propanolol oxprenolol Δ body weight[g] −5.51 ± 0.34 −5.10 ± 0.35 −5.89 ± 0.42 −5.59 ± 0.48 Δ lean mass [g]−4.31 ± 0.26  −3.71 ± 0.27*  −4.89 ± −0.26 −4.67 ± 0.42 Δ fat mass [g]−1.64 ± 0.15 −1.91 ± 0.15 −1.82 ± 0.25 −1.49 ± 0.12 Average Δ body−153.7 ± 22.2  −121.6 ± 15.2  −127.6 ± 10.6  −123.6 ± 12.3  weight[mg/day] Average Δ lean −135.9 ± 19.5  −92.31 ± 15.84 −107.0 ± 7.4 −102.0 ± 10.7  mass [mg/day] Average Δ fat −35.6 ± 3.8  −50.1 ± 6.1*−43.9 ± 5.5  −33.1 ± 2.6  mass [mg/day] Heart [mg] 100.5 ± 3.4  103.5 ±2.8  104.0 ± 3.2  100.2 ± 3.2  gastrocnemius 47.7 ± 3.0 55.2 ± 3.0 52.4± 3.3 52.2 ± 2.3 [mg] soleus [mg]  5.85 ± .022  5.47 ± 0.39  5.60 ± 0.28 4.99 ± 0.36* EDL [mg]  6.94 ± 0.25  6.71 ± 0.32  7.11 ± 0.37  7.24 ±0.41 BAT [mg] 41.2 ± 2.4  53.7 ± 2.9** 45.1 ± 2.9 40.6 ± 2.8 10 mg/kg/d20 mg/kg/d 10 mg/kg/d 20 mg/kg/d R-oxprenolol R-oxprenolol S-oxprenololS-oxprenolol Δ body weight [g] −6.36 ± 0.39 −5.21 ± 0.39 −5.40 ± 0.43−5.56 ± 0.47 Δ lean mass [g] −5.11 ± 0.32 −4.60 ± 0.28 −3.31 ±0.33*^(###) −4.78 ± 0.41 Δ fat mass [g] −1.71 ± 0.15 −1.59 ± 0.15 −1.26± 0.14 −1.56 ± 0.18 Average Δ body −146.1 ± 11.1  −111.0 ± 9.4   −123 ±11.6 −99.4 ± 9.7^(p=0.064) weight [mg/day] Average Δ lean −125.8 ± −12.7−96.6 ± 6.4  −89.6 ± 9.1* −93.3 ± 7.5* mass [mg/day] Average Δ fat mass−38.3 ± 4.2  −32.6 ± 3.0  −29.4 ± 3.7 −29.8 ± 3.6 [mg/day] Heart [mg]101.2 ± 2.7  100.7 ± 3.8  108.6 ± 5.8 104.1 ± 3.5 gastrocnemius [mg]50.8 ± 3.3 47.0 ± 2.6  55.1 ± 4.0  50.1 ± 2.9 soleus [mg]   4.49 ±0.36**  5.49 ± 0.34  5.89 ± 0.35  6.42 ± 0.39 EDL [mg]  6.53 ± 0.47 5.89 ± 0.31*  7.18 ± 0.34  7.79 ± 0.29*^($+++) BAT [mg] 44.5 ± 3.4 43.3± 4.1  46.8 ± 3.5  43.7 ± 2.3 Δ: delta, average Δ [mg/day]: averagedelta per day alive after disease onset, EDL: extensor digitorum longus,BAT: brown adipose tissue, *p < 0.05, **p < 0.01 vs placebo, ^(###)p <0.001 vs 10 mg/kg/d propanolol, ^($)p < 0.05 vs 20 mg/kg/d R-oxprenolol,⁺⁺⁺p < 0.001 vs 30 mg/kg/d rilutek

TABLE 8 Data for male mice administered with S-oxprenolol, R-oxprenolol,rilutek, propanolol, oxprenolol (racemic), or placebo. 10 mg/kg/d 20mg/kg/d placebo 30 mg/kg/d rilutek propanolol oxprenolol Δ body weight[g] −6.81 ± 0.54 −5.91 ± 0.43 −6.11 ± 0.54 −5.94 ± 0.77 Δ lean mass [g]−5.44 ± 0.39  −4.19 ± 0.38* −5.06 ± 0.37 −5.64 ± 0.68 Δ fat mass [g]−1.66 ± 0.27 −2.09 ± 0.22 −1.99 ± 0.26 −1.33 ± 0.13 Average Δ body−215.8 ± 36.4  −120.4 ± 17.9* −142.7 ± 15.9  −124.8 ± 20.7  weight[mg/day] Average Δ lean −178.1 ± 31.9   −87.4 ± 21.1* −118.6 ± 10.6 −119.4 ± 17.7  mass [mg/day] Average Δ fat mass −40.5 ± 6.8  −57.5 ±11.3 −51.9 ± 6.9  −28.3 ± 3.1  [mg/day] Heart [mg] 117.9 ± 3.4  115.6 ±2.4  113.5 ± 4.6  110.2 ± 2.9  gastrocnemius [mg] 57.1 ± 5.3 58.3 ± 4.963.3 ± 3.6 54.7 ± 3.9 soleus [mg]  6.03 ± 0.32  5.72 ± 0.64  5.63 ± 0.38 5.21 ± 0.51 EDL [mg]  7.83 ± 0.32  7.20 ± 0.51  7.94 ± 0.55  7.49 ±0.72 BAT [mg] 44.9 ± 3.9 54.8 ± 3.9 48.7 ± 5.1 45.7 ± 3.6 10 mg/kg/d 20mg/kg/d 10 mg/kg/d 20 mg/kg/d R-oxprenolol R-oxprenolol S-oxprenololS-oxprenolol Δ body weight [g] −6.515 ± 0.65   −5.53 ± 0.57  −6.57 ±0.57  −6.36 ± 0.67 Δ lean mass [g]  −5.55 ± −0.47  −5.12 ± 0.38  −3.67 ±0.46**^(#)  −5.34 ± 0.56 Δ fat mass [g] −1.57 ± 0.21  −1.48 ± 0.16 −1.44 ± 0.19  −1.78 ± 0.28 Average Δ body −153.5 ± 16.1  −116.0 ± 13.7*−150.3 ± 14.5 −115.7 ± 12.6* weight [mg/day] Average Δ lean −129.7 ±9.9  −106-4 ± 8.5 −115.1 ± 13.9  −95.8 ± 10.6* mass [mg/day] Average Δfat mass −37.4 ± 6.4   −29.9 ± 3.5  −33.6 ± 5.7  −32.1 ± 5.4 [mg/day]Heart [mg] 107.4 ± 3.4*  112.0 ± 4.1  122.6 ± 8.8  112.4 ± 4.5gastrocnemius [mg] 53.8 ± 5.1  49.9 ± 3.0  59.1 ± 6.6  53.1 ± 4.3 soleus[mg]  4.74 ± 0.51*  5.84 ± 0.45  6.04 ± 0.53  6.58 ± 0.61 EDL [mg]  6.59± 0.61  5.81 ± 0.42***  7.28 ± 0.47  8.15 ± 0.39^($$$) BAT [mg] 46.7 ±4.9  53.9 ± 6.8  53.2 ± 5.0  46.5 ± 3.0 Δ: delta, average Δ [mg/day]:average delta per day alive after disease onset, EDL: extensor digitorumlongus, BAT: brown adipose tissue, *p < 0.05, **p < 0.01, ***p < 0.001vs placebo, ^(#)p < 0.05 vs 10 mg/kg/d propanolol, ^($$$)p < 0.001 vs 20mg/kg/d R-oxprenolol

TABLE 9 Data for female mice administered with S-oxprenolol,R-oxprenolol, rilutek, propanolol, oxprenolol (racemic), or placebo. 10mg/kg/d 20 mg/kg/d placebo 30 mg/kg/d rilutek propanolol oxprenolol Δbody weight [g] −4-55 ± 0.32 −4.49 ± 0.46 −5.66 ± 0.66 −5.27 ± 0.61 Δlean mass [g] −3.42 ± 0.25 −3.31 ± 0.37  −4.70 ± 0.37** −3.76 ± 0.42 Δfat mass [g] −1.61 ± 0.15 −1.76 ± 0.21 −1.65 ± 0.44 −1.64 ± 0.21 AverageΔ body −97.3 ± 20.6 −122.9 ± 25.7  −111.3 ± 13.2  −122.5 ± 14.7  weight[mg/day] Average Δ lean −84.3 ± 11.9 −96.9 ± 24.2 −91.2 ± 8.3  −85.8 ±11.6 mass [mg/day] Average Δ fat mass −33.2 ± 4.6  −42.2 ± 6.1  −30.9 ±8.3  −37.5 ± 3.7  [mg/day] Heart [mg] 86.1 ± 1.5 91.4 ± 2.3  93.8 ± 2.7*89.5 ± 2.4 gastrocnemius [mg] 21.2 ± 2.9  54.1 ± 3.8** 40.6 ± 3.3 49.5 ±2.1 soleus [mg]  5.72 ± 0.30  5.26 ± 0.48  5.57 ± 0.43  4.76 ± 0.52 EDL[mg]  6.29 ± 0.28  6.28 ± 0.39  6.21 ± 0.37  6.97 ± 0.36 BAT [mg] 38.8 ±2.9  53.7 ± 4.5* 41.2 ± 2.2 35.2 ± 4.1 10 mg/kg/d 20 mg/kg/d 10 mg/kg/d20 mg/kg/d R-oxprenolol R-oxprenolol S-oxprenolol S-oxprenolol Δ bodyweight [g] −6.19 ± 0.42 −4.85 ± 0.55  −4.51 ± 0.55 −4.57 ± 0.55 Δ leanmass [g]  −3.76 ± 0.41* −4.55 ± 0.37  −3.99 ± 0.37^(##) −3.97 ± 0.49 Δfat mass [g] −1.87 ± 0.22 −1.71 ± 0.26  −1.17 ± 0.21^(p=0.059) −1.29 ±0.17 Average Δ body −137.4 ± 15.5  −105.2 ± 13.1  −103.3 ± 16.1 −82.0 ±13.6 weight [mg/day] Average Δ lean −121.3 ± 25.7  −85.2 ± 9.1   −69.2 ±10.8  90.7 ± 10.9 mass [mg/day] Average Δ fat mass −41.4 ± 5.3  −35.6 ±5.0   −25.9 ± 4.8 −26.8 ± 4.4⁺ [mg/day] Heart [mg]  94.4 ± 3.4* 88.5 ±4.6  92.3 ± 3.2^(p=0.064)  92.8 ± 3.0* gastrocnemius [mg] 47.5 ± 4.143.6 ± 4.2  50.5 ± 4.0*^(p=0.060 vs propanolol)  46.2 ± 3.9 soleus [mg] 4.23 ± 0.51*  5.09 ± 0.52  5.71 ± 0.48  6.15 ± 0.30 EDL [mg]  6.45 ±0.75  5.98 ± 0.47  7.03 ± 0.51  7.29 ± 0.42*^($) BAT [mg] 42.1 ± 4.632.6 ± 1.9  39.4 ± 4.2  37.1 ± 2.9 Δ: delta, average Δ [mg/day]: averagedelta per day alive after disease onset, EDL: extensor digitorum longus,BAT: brown adipose tissue, *p < 0.05, **p < 0.01, ***p < 0.001 vsplacebo, ^(##)p < 0.01 vs 1.0 mg/kg/d propanolol, ^($)p < 0.05 vs 20mg/kg/d R-oxprenolol, ⁺p < 0.05 vs 30 mg/kg/d rilutek

1. A method of treating amyotrophic lateral sclerosis in an individualhaving amyotrophic lateral sclerosis, comprising administering to theindividual an effective amount of a composition comprising a betablocker or a pharmaceutically acceptable salt thereof, wherein betablocker has one chiral center and the composition is enantiomericallyenriched for the S-enantiomer.
 2. A method of prolonging survival of anindividual having amyotrophic lateral sclerosis, comprisingadministering to the individual an effective amount of a compositioncomprising a beta blocker or a pharmaceutically acceptable salt thereof,wherein beta blocker has one chiral center and the composition isenantiomerically enriched for the S-enantiomer.
 3. A method of delayingthe development of amyotrophic lateral sclerosis in an individual havingamyotrophic lateral sclerosis, comprising administering to theindividual an effective amount of a composition comprising a betablocker or a pharmaceutically acceptable salt thereof wherein betablocker has one chiral center and the composition is enantiomericallyenriched for the S-enantiomer.
 4. A method of preventing loss of leanmass of an individual having amyotrophic lateral sclerosis, comprisingadministering to the individual an effective amount of a compositioncomprising a beta blocker or a pharmaceutically acceptable salt thereof,wherein beta blocker has one chiral center and the composition isenantiomerically enriched for the S-enantiomer.
 5. A method ofpreventing muscle wasting of an individual having amyotrophic lateralsclerosis, comprising administering to the individual an effectiveamount of a composition comprising a beta blocker or a pharmaceuticallyacceptable salt thereof, wherein beta blocker has one chiral center andthe composition is enantiomerically enriched for the S-enantiomer.
 6. Amethod of improving quality of life in an individual having amyotrophiclateral sclerosis, comprising administering to the individual aneffective amount of a composition comprising a beta blocker or apharmaceutically acceptable salt thereof, wherein beta blocker has onechiral center and the composition is enantiomerically enriched for theS-enantiomer.
 7. The method of claim 1, wherein the beta blocker isoxprenolol or a pharmaceutically acceptable salt thereof.
 8. The methodof claim 7, wherein the composition comprises an enantiomeric excess ofat least about 50% of S-oxprenolol.
 9. The method of claim 8, whereinthe composition comprises an enantiomeric excess of at least about 80%of S-oxprenolol.
 10. The method of claim 9, wherein the compositioncomprises an enantiomeric excess of at least about 99% of S-oxprenolol.11. The method of claim 10, wherein the composition comprises anenantiomeric excess of at least 99.9% of S-oxprenolol.
 12. The method ofclaim 1, wherein the amyotrophic lateral sclerosis is sporadicamyotrophic lateral sclerosis.
 13. The method of claim 1, wherein theamyotrophic lateral sclerosis is familial amyotrophic lateral sclerosis.14. The method of claim 1, wherein the amyotrophic lateral sclerosis isWestern Pacific amyotrophic lateral sclerosis.
 15. The method of claim1, wherein the amyotrophic lateral sclerosis is juvenile amyotrophiclateral sclerosis.
 16. The method of claim 1, wherein the amyotrophiclateral sclerosis is Hiramaya Disease.
 17. The method of claim 1,wherein the amyotrophic lateral sclerosis is progressive bulbar palsy(PBP), progressive muscular atrophy (PMA), primary lateral sclerosis(PLS), or ALS with multi-system involvement.
 18. The method of claim 1,wherein the composition is administered orally.
 19. The method of claim1, wherein the amount of S-oxprenolol in the composition is about 80 toabout 160 mg daily.
 20. The method of claim 1, wherein the compositionis administered daily or twice daily.
 21. A kit comprising apharmaceutical composition comprising a composition comprising a betablocker or a pharmaceutically acceptable salt thereof wherein betablocker has one chiral center and the composition is enantiomericallyenriched for the S-enantiomer; and a pharmaceutically acceptablecarrier.
 22. The kit of claim 21, wherein the beta blocker isoxprenolol.